new research in psoriasis

Revolutionary advances in psoriasis treatment: unveiling new therapeutic approaches

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In a recent review published in Signal Transduction and Targeted Therapy , researchers reviewed existing data on psoriasis etiopathogenesis and treatment.

Psoriasis is a prevalent, chronic, inflammatory skin condition that affects people, healthcare institutions, and society. Despite advancements in therapy, the processes behind less predominant types remain a mystery.

Severe side effects and illness recurrence after therapy discontinuation are concerning. Understanding psoriasis pathophysiology is critical for new research findings, therapeutic approaches, and extended clinical treatment choices.

About the review

In the present review, researchers elucidated the biological mechanisms underlying psoriasis development and described current treatment options and those undergoing clinical trials.

Biological pathways and signaling mechanisms underlying Psoriasis

Psoriasis is a chronic skin condition characterized by increased immune cells such as T helper 1 (Th1), Th17, and Th22 cells.

These cells secrete interleukin-22 (IL-22), which binds to IL-22 receptors on target cells, activating downstream signals in keratinocytes, inducing the production of antimicrobial proteins, and inhibiting keratinocyte differentiation, resulting in acanthosis, a typical psoriasis-like inflammation of the epidermis.

Tumor necrosis factor-alpha (TNF-α) may boost the impact of IL-22. Tumor necrosis factor-interleukin 23-interleukin 17 pathways are associated with psoriasis pathophysiology, particularly plaque psoriasis.

Dendritic cells (DCs) are the primary secretors of interleukin 12 and interleukin 23, with ribonucleic acid (RNA0 expression of p19 and p40 rising significantly in psoriasis lesions.

IL-23 operates on T lymphocytes, especially helper T [cluster of differentiation 4+ (CD4+] cells, through a cell-based receptor complex composed of transmembrane proteins IL-12R1 and IL-23R. IL-23 stimulates the interleukin-17 production, a critical cytokine implicated in psoriasis pathophysiology.

IL-17A, C, and F are associated with psoriasis due to their elevated levels in psoriasis lesions. TNF-α primarily works on target cells via two kinds of TNF receptors, TNFRI (p55) and TNF-RII (p75). It dramatically reduces plasmacytoid dendritic cell (pDC) IFN-secretion, promoting pDC maturation to a more conventional dendritic cell phenotype capable of producing IL-23. TNF-α also works with IL-17A to coregulate psoriasis-related cytokines and keratinocyte genes, influencing keratinocyte function.

C-C Motif Chemokine Ligand 20 (CCL20), also known as macrophage inflammatory protein 3 (MIP-3), is a crucial chemokine in psoriasis; however, it only binds to the C-C chemokine receptor 6 ( CCR6).

Scratching or trypsinization can boost CCL20 synthesis by keratinocytes in psoriatic lesions and release CCR6+ Th17 cells, which generate IL-17A and further promote CCL20 selection. Metabolic alterations have been implicated in psoriasis pathogenesis, especially those involved in regulating keratinocytes and associated immune cells.

Treatment targeting metabolic variables may be a viable option for managing psoriasis. Psoriasis is distinguished by increased CD147 on neutrophils, which causes chemotaxis. The nuclear factor kappa B (NF-κB) pathway regulates keratinocyte and immune cell proliferation and differentiation.

Wnt signaling is also altered, with Wnt-5a increased and WIF-1 downregulated in psoriatic lesions. L-type amino acid transporter 1 (LAT1)-mediated amino acid absorption inhibition may aid in managing skin inflammation. Lysophosphatidic acid (LPA), phosphatidylinositol (PI), and LysoPC, which are involved in glycerophospholipid metabolism, are elevated in the plasma of psoriasis patients.

Targeted therapies for psoriasis

Psoriasis treatment aims to reduce inflammation, remove skin lesions, enhance quality of life, and avoid complications by eliminating lesions, lowering itching, and improving the patient's quality of life.

Treatment options for mild psoriasis include topical corticosteroids, calcipotriol, and their combination. In moderate-severe psoriasis cases unresponsive to topical treatments, oral drugs such as retinoids, cyclosporine, and methotrexate are used.

Methotrexate has been licensed by the Food and Drug Administration (FDA) for over 50 years. Still, cyclosporine is used for severe psoriasis, although it is associated with various adverse effects such as renal toxicity.

Acitretin is used to manage pustular and erythrodermic psoriasis; however, it is contraindicated for pregnant individuals due to its teratogenicity. Phototherapy, which includes psoralen and ultraviolet-A (PUVA), narrow-band UVB (NB-UVB), and wide-band UVB, is an essential therapeutic option for moderate to severe psoriatic lesions.

TNF-α inhibitors, IL-17 inhibitors, IL-12/IL-23p40 inhibitors, IL-23 inhibitors, IL-36/IL-1 inhibitors, Janus kinase (JAK) inhibitors, Phosphodiesterase 4 (PDE4) inhibitors, IL-22 inhibitors, and IFN inhibitors are examples of biologics used to treat psoriasis.

RORγT-targeted drugs (JTE-451, mesenchymal stem cells), aryl hydrocarbon receptor (AhR)-targeted agents (topical tapinarof), and sphingosine 1-phosphate receptor 1 (S1PR1)-targeted agents (Ponesimod) are among the therapies under clinical trials. Some medications can modify deoxyribonucleic acid (DNA) methylation, impacting inflammation and immunological responses, making it a potential therapeutic target for psoriasis.

Overall, the review findings highlighted altered signaling pathways in psoriasis pathogenesis, which could be targeted to develop novel and effective interventions to reduce the health burden of the disease.

While progress has been made in understanding and treating psoriasis, further research is needed to determine if genetic indicators and biomarkers can predict early diagnosis and intervention. Additionally, there is a lack of comprehensive understanding of metabolic effects in psoriasis.

Guo, J., Zhang, H., Lin, W.  et al.  (2023) Signaling pathways and targeted therapies for psoriasis,  Sig Transduct Target Ther . doi : https://doi.org/10.1038/s41392-023-01655-6 .  https://www.nature.com/articles/s41392-023-01655-6

Tags: Amino Acid , CCL20 , CD4 , Cell , Cell Proliferation , Chemokine , Chronic , Cyclosporine , Cytokine , Cytokines , Dendritic Cell , DNA , Drugs , Epidermis , Food , Genes , Genetic , Healthcare , Inflammation , Interleukin , Kinase , Ligand , Macrophage , Mesenchymal Stem Cells , Metabolism , Methotrexate , Necrosis , Neutrophils , Pathophysiology , PDE4 , Phenotype , Phototherapy , Proliferation , Protein , Psoriasis , Psoriatic , Receptor , Research , Ribonucleic Acid , Skin , Stem Cells , Tumor , Tumor Necrosis Factor

Pooja Toshniwal Paharia

Pooja Toshniwal Paharia is an oral and maxillofacial physician and radiologist based in Pune, India. Her academic background is in Oral Medicine and Radiology. She has extensive experience in research and evidence-based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

Please use one of the following formats to cite this article in your essay, paper or report:

Toshniwal Paharia, Pooja Toshniwal Paharia. (2023, November 29). Revolutionary advances in psoriasis treatment: unveiling new therapeutic approaches. News-Medical. Retrieved on September 25, 2024 from https://www.news-medical.net/news/20231129/Revolutionary-advances-in-psoriasis-treatment-unveiling-new-therapeutic-approaches.aspx.

Toshniwal Paharia, Pooja Toshniwal Paharia. "Revolutionary advances in psoriasis treatment: unveiling new therapeutic approaches". News-Medical . 25 September 2024. <https://www.news-medical.net/news/20231129/Revolutionary-advances-in-psoriasis-treatment-unveiling-new-therapeutic-approaches.aspx>.

Toshniwal Paharia, Pooja Toshniwal Paharia. "Revolutionary advances in psoriasis treatment: unveiling new therapeutic approaches". News-Medical. https://www.news-medical.net/news/20231129/Revolutionary-advances-in-psoriasis-treatment-unveiling-new-therapeutic-approaches.aspx. (accessed September 25, 2024).

Toshniwal Paharia, Pooja Toshniwal Paharia. 2023. Revolutionary advances in psoriasis treatment: unveiling new therapeutic approaches . News-Medical, viewed 25 September 2024, https://www.news-medical.net/news/20231129/Revolutionary-advances-in-psoriasis-treatment-unveiling-new-therapeutic-approaches.aspx.

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Psoriasis Therapies in 2024 and Beyond

This article will highlight recently approved psoriasis therapies that will shape the 2024 treatment landscape and provide some exciting updates in the psoriasis management market this coming year and beyond.

Decades ago, psoriasis was still primarily considered a problem with hyperproliferation of the epidermis. Given the antiquated understanding of this disease pathophysiology, traditional oral immunosuppressive agents were used for moderate to severe presentations. Recent research into the pathophysiology of psoriasis has highlighted the importance of the immune-mediated nature of this very common inflammatory skin disease. There now exists a clear mechanism down to the molecular level regarding which cytokines are implicated in the pathophysiology of psoriatic disease. When considering these different molecular signaling pathways, IL-23–mediated activation of the Th17 pathway is hypothesized to be the main contributor to the inflammation seen in psoriasis. 1 Due to its important role in the pathophysiology of psoriasis, IL-23 has been referred to as the master cytokine in psoriatic disease by many clinicians and researchers. Other important cytokines include TNF-α and IL-17. The fact that biologic agents interact with a specific cytokine (such as TNF-α, IL-17, or IL-23) in a targeted manner has revolutionized the capacity to manage psoriasis compared with the era of a more generalized immunosuppression reflected by the traditional oral medications (eg, methotrexate, cyclosporine, and acitretin). This represents an improved treatment paradigm where targeted immunomodulation has resulted in a great enhancement in both safety and efficacy for the biologic agents.

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There are now more than 13 FDA-approved biologic options for moderate to severe psoriasis. Additionally, there have been new approvals for oral and topical therapies for psoriasis, including a topical first-in-class mechanism of action for psoriatic skin lesions. Given that psoriasis affects more than 7 million adults in the US, the therapeutic landscape is constantly evolving. 2 It is estimated that the psoriasis management market will be worth nearly $121 billion by the end of 2024. 3 This article will highlight recently approved psoriasis therapies that will shape the 2024 treatment landscape and provide some exciting updates in the psoriasis management market this coming year and beyond. It will also highlight how biosimilar medications will affect the field for years to come and cover new updates in the management of pediatric psoriasis.

The newest biologic agent for psoriasis, bimekizumab (Bimzelx), was approved by the FDA on October 18, 2023, for the management of moderate to severe psoriasis. Bimekizumab is unique in that it blocks both the IL-17A and IL-17F cytokines. The other IL-17 antagonists approved to manage psoriasis either only block IL-17A (ixekizumab and secukinumab) or block the IL-17 receptor (brodalumab). In findings from the phase 3 BE READY trial (NCT03410992), which studied bimekizumab in the management of moderate to severe psoriasis, 91% of 349 patients receiving this medication at 320 mg every 4 weeks achieved a Psoriasis Area and Severity Index (PASI) score of 90 compared with 1% of 86 patients receiving placebo. 4 In findings from the phase 3 BE OPTIMAL trial (NCT03895203), which studied bimekizumab in the management of psoriatic arthritis (for biologic-naive patients), significantly more patients receiving bimekizumab (44%) reached American College of Rheumatology 50% response vs those receiving placebo (10%). 5 “Head-to-head studies with bimekizumab vs currently FDA-approved biologic agents, including adalimumab, secukinumab, and ustekinumab, have highlighted the rapid onset of action of this new biologic medication. Even before the second dose, this is a significant PASI response, making this a great option for a patient whose main concern is rapid improvement with infrequent dosing compared with some competitors. Bimekizumab’s unique mechanism of action [IL-17A/F] is a novel and exciting addition to the current biologic landscape for psoriasis,” G. Michael Lewitt, MD, FAAD, a board-certified dermatologist at Rosealind Franklin-Chicago Medical School in Chicago, Illinois, said.

Pooled safety analysis from phase 2 and phase 3 showed that nasopharyngitis, oral candidiasis, and upper respiratory tract infection were the most common treatment-emergent adverse events reported with bimekizumab. IL-17 is involved in mucosal host defenses against fungal infections; therefore, anti–IL-17 biologics can be associated with an increased risk of oral mucocutaneous candidiasis. 6 Of the patients in the phase 2/3 trials, 15.4% reported an oral candidiasis event in the first year and 9.1% reported it during the second year. These rates are higher when compared with the other IL-17 antagonists.

Although not considered a new biologic, adalimumab will greatly affect the 2024 psoriasis treatment landscape because generic versions are approved for the management of adult plaque psoriasis. These include the 9 following FDA-approved agents: adalimumab-aacf (Idacio), adalimumab-fkjp (Hulio), adalimumab-adbm (Cyltezo), adalimumab-bwwd (Hadlima), adalimumab-adaz (Hyrimoz), adalimumab-aaty (Yuflyma), adalimumab-aqvh (Yusimry), adalimumab-afzb (Abrilada), and adalimumab-atto (Amjevita). 7 According to the FDA, biosimilars must prove bioequivalence and be tested by way of clinical trials to ensure they will exhibit no significant differences to their parent product. 8

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AAD 2023 Focus on Psoriasis: Biologics Take Center Stage

At the 2023 Annual Meeting of the American Academy of Dermatology (AAD), several research studies on the use of biologics in psoriasis were presented, highlighting the efficacy and safety of these agents in patients with the inflammatory skin disease.

Tildrakizumab Deemed Safe and Effective in Plaque Psoriasis

Treatment with tildrakizumab was associated with high efficacy rates and the anti-interleukin (IL)-23 p19 monoclonal antibody featured a favorable safety profile among patients with moderate to severe plaque psoriasis, according to the results of a study presented at the meeting. 1

The study consisted of pooled analyses of the phase 3 reSURFACE 1 (ClinicalTrials.gov Identifier: NCT01722331 ) and reSURFACE 2 (ClinicalTrials.gov Identifier: NCT01729754 ) trials. In these studies, patients with moderate to severe plaque psoriasis received treatment with tildrakizumab 100 mg at weeks 0 and 4 and then every 12 weeks thereafter. Clinical improvement in disease activity was evaluated by the proportions of patients who achieved ≥75%, ≥90%, and ≥100% Psoriasis Area and Severity Index (PASI) improvement (PASI 75, 90, and 100 response), as well as Physician’s Global Assessment (PGA) score of 0 or 1 with an at least 2 grade reduction (PGA 0/1) from baseline.

Across all age quartiles (18-36 years, 36-45 years, 45-55 years, and 55-82 years), the proportions of patients who achieved PASI 75, PASI 90, and PASI 100 responses increased over time and peaked at week 28. More than half of patients achieved PASI 75 response by week 12, with continued improvements observed through week 28. A greater proportion of patients aged 18 to 35 years achieved PASI 100 response by week 28 (29.5%). Additionally, the investigators observed similar percentages of patients across all age quartiles who achieved PGA 0/1 with an at least 2 grade decrease from baseline by week 28.

“Median PASI scores trended down quickly for all groups, eventually settling on very low numerical values, which underscores the high level of clearance that the vast majority of patients will experience,” explained study researcher George Han MD, PhD, of the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York.

With respect to safety, the most frequently reported treatment-emergent adverse events (TEAEs) included arthralgia, diarrhea, headache, and nasopharyngitis. Severe TEAEs were observed in up to 5% of patients, but the investigators reported a higher frequency of these severe events in patients aged 45 years and older.

“I think tildrakizumab has always stood out due to its safety,” said Dr Han. “It’s reassuring to see that this is a consistent finding regardless of how the data is cut.”

Dr Han added that a strength of the IL-23 inhibitor class includes the lack of significant contraindications. “It’s an easy decision to start one of these medications, and, within the class, tildrakizumab is notable for its safety and reliability,” he explained.

In terms of future research, Dr Han noted that he would like to see more long-term data across age, weight, and prior treatment groups to further “fill out the story” of the efficacy of tildrakizumab. “I am enthused by numerous real-world studies that have shown higher efficacy rates of tildrakizumab in clinical trials, which is very impressive indeed as we often see the opposite effect,” he added.

Anti-IL-17A Improves Psoriasis in Real-Life Practice

Patients with moderate to severe psoriasis experience benefit with anti-IL-17A biologics, regardless of whether they have previously undergone treatment with a biologic with a different mechanism of action, according to a real-world study presented by Saakshi Khattri, MD, director of the Center for Connective Tissue Diseases at the Icahn School of Medicine at Mount Sinai in New York, New York. 2 “Overall, [the findings] reconfirmed what we know via clinical trials and via what we see in our practices,” said Dr Khattri. “When we use all biologics, they work to clear or improve psoriasis.”

The Psoriasis Study of Health Outcomes (PSoHO) included adult patients with psoriasis who either initiated their first biologic therapy (n=1127) or switched biologics (n=645) for the treatment of the disease. Among biologic-naive patients, a greater proportion achieved PASI ≥90 and/or static PGA 0/1 with anti-IL-17A biologics (77%) vs biologics with other mechanisms of action (61%). Among biologic-experienced patients, a greater proportion also achieved PASI ≥90 and/or static PGA 0/1 with an anti-IL-17A agent (65%) vs biologic agents with different mechanisms of action (56%). No comparative analyses were performed, however, and the researchers did not adjust for measured confounders.

Dr Khattri noted that the real-world findings are particularly impactful for practicing clinicians, as they provide “another piece of information” regarding optimal biologic selection for individual patients with psoriasis. “Real-world [data] are always important, as that is close to what we as prescribers see in our offices,” she said, adding that to have data on how agents with specific mechanisms of action fare over others “is helpful in making an informed decision.”

Deucravacitinib Shows Promising Efficacy in Plaque Psoriasis

A study presented at AAD 2023 reported long-term findings from the phase 3 POETYK PSO Program, which included patients with moderate to severe plaque psoriasis who underwent treatment with the oral allosteric tyrosine kinase (TYK) 2 inhibitor deucravacitinib. 3 The study findings were presented by Richard Warren, MD, professor of Dermatology and Therapeutics and Honorary Consultant Dermatologist at the University of Manchester in the United Kingdom.

The study analyzed long-term clinical outcomes in patients with approximately 2 years of continuous exposure to the TYK2 inhibitor. In total, 265 patients with moderate to severe plaque psoriasis received continuous treatment with deucravacitinib from day 1 in the POETYK-PSO-1 trial (ClinicalTrials.gov Identifier: NCT03624127 ) to week 112 in the POETYK PSO-LTE long-term extension study (ClinicalTrials.gov Identifier: NCT04036435 ).

The study subdivided the cohort into biologic-naive patients (n=157), anti-tumor necrosis factor (anti-TNF)-experienced patients (n=36), and anti-IL-17/anti-IL-23-experienced patients (n=72). At week 12, high clinical responses to deucravacitinib were observed across all patient subgroups, according to PASI and static PGA scores.

Biologics for Prevention of Psoriatic Arthritis

Another study looked at the effects of biologics on preventing the development of psoriatic arthritis in patients with psoriasis. 4 The retrospective cohort study compared the incidence of psoriatic arthritis among patients with psoriasis who switched from phototherapy to biologics (n=623) vs those who continued phototherapy (n=1182).

The capped follow-up period was 10 years. Overall, the incidence rate per 1000 person-years for psoriatic arthritis was 49.19. The incidence rates for psoriatic arthritis in the phototherapy and biologic cohorts were 56.83 and 38.77, respectively, a difference that was statistically significant in a multivariable-adjusted analysis (adjusted hazard ratio, 0.69; 95% CI, 0.55-0.88; P =.003).

When asked to comment on the findings, David M. Pariser, MD, of Pariser Dermatology in Norfolk, Virginia, said that it has been widely known that psoriasis is often accompanied with a number of comorbidities, including psoriatic arthritis.

“Psoriatic arthritis is a crippling condition if not treated,” said Dr Pariser, who was not involved in the study. “Dermatologists who see patients with psoriasis earlier on in their course can be a significant help if they’re able to identify early signs of psoriatic arthritis and put people on biologics, which do tend not only to help prevent worsening of disease, but in some cases with some of the biologics has been shown to actually reverse some of the damage to the joints.”

Further Clinical Perspectives

According to Dr Pariser, the development of biologics revolutionized the entire treatment landscape for psoriasis by allowing for better clearance of the disease in many patients. “And for most people, these agents are much safer than the traditional treatments that were used before biologics became available,” he added.

Over the past few years, biologic agents have improved in terms of their efficacy and safety, Dr Pariser commented. “All of the psoriasis clinical trials measure quality of life using some standardized validated measure, and a significant improvement in quality of life occurs.”

Dr Pariser added that given their demonstrated efficacy and safety, biologics have now become standard of care in the treatment of psoriasis. “I’ve been around long enough to remember what it was like before biologics, and it certainly is a much better world now because of it,” he concluded.

Disclosure: The POETYK trials were supported by Bristol Myers Squibb, the PSoHO trial was supported by Eli Lilly and Company, and the reSURFACE 1 and reSURFACE 2 trials were supported by Merck. The authors reported financial affiliations with the pharmaceutical industry.

April 1, 2022

References:

• Elewski B, Han G, Rozzo SJ, et al. Insights into the efficacy and safety of tildrakizumab in patients with moderate-to-severe plaque psoriasis across age quartiles: pooled analyses from the Phase 3 reSURFACE 1 and reSURFACE 2 trials . Poster presentation at: AAD 2023; March 17-21, 2023; New Orleans, LA. Poster 42297.
• Khattri S, Gooderham M, Reich A, et al. The Psoriasis Study of Health Outcomes (PSoHO) in biologic-naïve and -experienced patients: a post-hoc analysis of patients receiving treatment according to US labels . Poster presentation at: AAD 2023; March 17-21, 2023; New Orleans, LA. Poster 43054.
• Warren RB, Armstrong AW, Imafuku S, et al. Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, in moderate to severe plaque psoriasis: 2-year efficacy by prior biologic treatment in the phase 3 POETYK PSO program . Poster presentation at: AAD 2023; March 17-21, 2023; New Orleans, LA. Poster 43879.
• Miao K, Huang M, Xepoleas M, et al. Do biologics for psoriasis prevent the development of psoriatic arthritis? A population-based study . Poster presentation at: AAD 2023; March 17-21, 2023; New Orleans, LA. Poster 42744.

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• Published: 24 January 2022

Advances in the pathogenesis of psoriasis: from keratinocyte perspective

• Xue Zhou 1 , 2   na1 ,
• Youdong Chen 1 , 2   na1 ,
• Lian Cui 1 , 2 ,
• Yuling Shi   ORCID: orcid.org/0000-0002-1273-7881 1 , 2 &
• Chunyuan Guo   ORCID: orcid.org/0000-0001-6769-1713 1 , 2  

Cell Death & Disease volume  13 , Article number:  81 ( 2022 ) Cite this article

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• Immunological disorders
• Mechanisms of disease

Psoriasis is a complex long-lasting inflammatory skin disease with high prevalence and associated comorbidity. It is characterized by epidermal hyperplasia and dermal infiltration of immune cells. Here, we review the role of keratinocytes in the pathogenesis of psoriasis, focusing on factors relevant to genetics, cytokines and receptors, metabolism, cell signaling, transcription factors, non-coding RNAs, antimicrobial peptides, and proteins with other different functions. The critical role of keratinocytes in initiating and maintaining the inflammatory state suggests the great significance of targeting keratinocytes for the treatment of psoriasis.

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Psoriasis is characterized by the excessive proliferation and abnormal differentiation of keratinocytes and infiltration of multiple inflammatory cells.

Keratinocytes are critical in psoriasis pathogenesis and participate in both the initiation and maintenance phases of psoriasis.

Various factors such as genetics, cytokines and receptors, metabolism, cell signaling, transcription factors, non-coding RNAs, antimicrobial peptides, etc. modulate the functions of keratinocytes and influence psoriasis.

Targeting those factors provides promising therapeutic strategies for psoriasis.

Open questions

What’s the key factor that modulates keratinocytes in psoriasis?

What’s the role of keratinocytes in the relapse of psoriasis?

Can we achieve higher anti-psoriasis efficacy based on treatment targeting keratinocytes more selectively and efficiently?

Introduction

Psoriasis is a chronic, inflammatory autoimmune skin disease affected by genetic and various environmental factors. It has been recognized as a significant public health burden and is estimated to affect ~125 million people globally and ~2–4% of the population in western countries [ 1 , 2 ]. Although the mortality rate of psoriasis is low, patients with psoriasis experience a significant impairment in life quality and a tremendous psychosocial burden.

Psoriasis is characterized by epidermal hyperplasia and dermal infiltration of immune cells. The pathogenesis of psoriasis is complicated, which involves the interplay between keratinocytes, immune cells, and other skin-resident cells. Over the last 2 decades, psoriasis has been considered as an immune cell-driven disease, and keratinocytes are just executors to perform the function of immune cells during psoriasis [ 3 ]. And the IL-23/IL-17 pathogenic axis is the key to drive psoriasis. Activation of plasmacytoid dendritic (pDCs) promotes myeloid dendritic cells (mDCs) maturation and production of TNF-α, IL-12, and IL-23, which leads to the activation of Th (T helper) 1 and Th17 and subsequent secretion of inflammatory cytokines, such as TNF-α, IL-17, IL-21, and IL-22. Keratinocytes are then activated by these cytokines (especially IL-17) and produce antimicrobial peptides, cytokines, and chemokines, contributing to the amplification of inflammation [ 1 , 4 ]. Multiple biologics targeting TNF-α, IL-23, and IL-17 have shown tremendous success in the treatment of psoriasis. However, the side effects, safety, loss of efficacy and recurrence after discontinuation of these biologics encourage researchers to explore novel therapeutic strategies. Emerging evidence has shown that keratinocytes could act as a trigger in psoriasis, and would be a promising target for psoriasis treatment [ 3 ].

In this extensive review, we aim to discuss the recent advances in the pathogenesis of psoriasis from keratinocyte perspective. We will discuss multiple factors modulating keratinocytes and how keratinocytes are affected and linked to the pathogenesis of psoriasis.

The role of keratinocytes in psoriasis pathogenesis

Keratinocytes play essential roles in both the initiation and maintenance phases of psoriasis (Fig. 1 ). As part of the innate immune system, keratinocytes can respond to multiple triggers. Stressed keratinocytes release self-nucleotides and antimicrobial peptides, thus promoting the activation of pDCs. Then mDCs is activated and matured by producing IFN-α, IFN-γ, TNF-α, and IL-1β [ 5 , 6 ].

This figure depicts the pathological process of psoriasis mainly from the keratinocyte perspective. Keratinocytes can be stimulated by initial triggers, and stressed keratinocytes release self-nucleotides and antimicrobial peptide, activate pDCs and subsequent mDCs, involving in the initiation phase of psoriasis. After cytokines stimulation, activated keratinocytes influence psoriasis pathology from aspects of inflammatory infiltration, epidermal hyperplasia, innate immunity, tissue reorganization, etc. pDCs plasmacytoid dendritic cells, mDCs myeloid dendritic cells, IFN interferon, TNF-α tumor necrosis factor-α, IL-1β interleukin-1β, Th1 T helper 1.

Besides participating in the initiation phase, keratinocytes also work as amplifiers of psoriatic inflammation during maintenance phase [ 7 ]. Once activated by proinflammatory cytokines synergistically, keratinocytes are highly proliferative and can produce copious chemokines (e.g. CXCL1/2/3, CXCL8, CXCL9/10/11, CCL2, and CCL20) to recruit leukocytes (such as neutrophils, Th17 cells, dendritic cells, and macrophages), antimicrobial peptides (e.g. S100A7/8/9/12, hBD2, and LL37) to induce innate immunity, and other inflammatory mediators to amplify inflammation. Moreover, keratinocytes, together with fibroblasts and endothelial cells, lead to tissue reorganization via activation and proliferation of endothelial cells and deposition of extracellular matrix [ 8 , 9 , 10 ]. The crosstalk between keratinocytes and immune cells especially Th17 cells results in the induction and maintenance of psoriasis with hyperproliferation and aberrant differentiation of keratinocytes, dilated and hyperplastic blood vessels, and infiltration of inflammatory cells like leukocytes [ 7 , 11 , 12 ].

Factors regulating psoriatic keratinocytes

Genetic regulation.

Epidemiologic studies indicate a strong genetic basis for psoriasis with a high heritability rate of 60–90% [ 13 ]. Over 80 psoriasis-susceptible loci have been identified, the strongest of which was the psoriasis-associated susceptibility locus 1 (PSORS1). Throughout these decades, there are at least 100 susceptibility genes for psoriasis identified, most of which are involved in adaptive immunity, innate immunity, and skin barrier function [ 13 , 14 ]. Some of the candidate causal genes are keratinocyte-associated, which will be discussed below and summarized in Table 1 .

Genomic studies linked the mediators of NF-κB pathway as disease susceptibility genes for psoriasis. For example, CARD14, encoding scaffold protein CARMA2 (CARD-containing MAGUK protein 2), is a NF-κB activator, which is mainly expressed in epidermal keratinocytes. Several genetic mutations of CARD14 (which maps to the psoriasis susceptibility locus 2 (PSORS2)) have been identified associated with psoriasis susceptibility [ 6 ]. To investigate the pathogenic role of CARD14 mutation in psoriasis, two groups generated two mouse models with patient-derived CARD14 gain-of-function mutations (a mutation in E138 (Card14 E138A/+ ) or a deletion of E138 (Card14 ∆E138A/+ )), respectively. Spontaneous psoriasis-like phenotype was developed in both models, indicating the CARD14 gain-of-function mutation is sufficient to drive the initiation of psoriasis [ 15 , 16 ]. Furthermore, CARD14 deficiency protected mice from IMQ- or IL-23-induced psoriasis-like dermatitis [ 15 , 17 ]. Mechanically, gain-of-function CARD14 mutations caused CARD14 aggregation and hyperactivation and enhanced CARD14-BCL10-MALT1 complex formation in keratinocytes, which results in constitutive activation of NF-κB and MAPK signaling pathway, subsequently leading to elevated expression of inflammatory cytokines, chemokines, and antimicrobial peptides and enhanced activation of IL23/IL-17A axis [ 15 , 16 , 18 ]. Of note, CARD14 serves as a key mediator in IL-23/IL-17A axis through interaction with ACT1-TRAP6 signaling complex [ 15 ].

In addition, the NF-κB inhibitors TNFAIP3 (TNF-α induced protein 3, encoding A20) and TNIP1 (TNFAIP3-interacting protein 1, encoding ABIN1) have been identified as susceptibility loci for psoriasis and keratinocyte-associated genes. TNFAIP3/A20 is a deubiquitinase that can be linked to the IkB kinase complex by TNIP1/ABIN1, thus preventing activation of NF-κB. TNFAIP3/A20 was decreased in the epidermis of psoriatic patients, and keratinocyte-specific deletion of TNFAIP3/A20 potentiates the pro-inflammatory genes expression of keratinocytes in psoriasis and other inflammatory disorders [ 19 ]. Global deletion of TNIP1/ABIN1 caused mice susceptible to the development psoriasis-like dermatitis induced by IMQ. Further investigation indicated TNIP1/ABIN1 deficiency in keratinocytes was sufficient to promote psoriasis inflammation, which disturbed IL-17-induced gene expression, and exaggerated chemokine and cytokine production [ 20 ]. Furthermore, the inhibitory effect of TNIP1/ABIN1 on psoriasis is mainly attributed to the suppression of inflammatory responses in keratinocytes rather than inhibiting keratinocyte proliferation [ 21 ].

Vascular endothelial growth factor A (VEGFA), the main epidermal-derived vessel-specific growth factor, is overexpressed in several inflammatory diseases, including psoriasis. The VEGFA gene is located at the PSORS1 locus, which is highly polymorphic and associated with psoriasis severity [ 22 ]. Transgenic mouse model overexpressing VEGFA in keratinocytes developed a spontaneous psoriasiform phenotype and inhibition of VEGFA reversed the psoriatic phenotype mediated by epidermal overexpression of VEGFA or epidermal deletion of c-Jun/JunB [ 23 , 24 , 25 , 26 ]. VEGFA works through its receptors Flt1 (VEGFR1) and Flk1 (VEGFR2) and its coreceptor Neuropilin 1 (Nrp1). Keratinocyte-specific deletion of Flt1 or Nrp1 diminished VEGFA-induced psoriasis, suggesting that VEGFA/Flt1/Nrp1 axis has an essential epidermal autonomous function in the pathogenesis of psoriasis [ 27 ]. Altogether, these results indicate the epidermal VEGFA signaling as a promising therapeutic target for psoriasis.

TRAF3 interacting protein 2 (TRAF3IP2) is another psoriasis susceptibility gene associated with keratinocytes. It encodes ACT1, which is an adaptor protein with ubiquitin ligase activity, and plays an essential role in the signal transduction downstream of IL-17A receptor. TRAF3IP2 silencing in keratinocytes enhanced cell differentiation and inhibited IL-17 response [ 28 ]. In vivo, loss of ACT1 inhibited IL-17 signaling pathway and protected mice from psoriasiform dermatitis induced by IMQ and IL-23 [ 28 , 29 ]. Interferon alpha-inducible protein 27 (IFI27) maps chromosome 14q32, which is located at a psoriasis susceptibility locus [ 30 ]. IFI27 was upregulated in the lesional skin of psoriatic patients and serves as a novel epidermal growth factors-stabilized protein in keratinocytes. Silencing IFI27 in keratinocytes caused cell cycle arrest and inhibited cell proliferation, and topical application of IFI27 siRNA ameliorated IMQ-induced epidermal hyperplasia in mice [ 31 ].

Except for mutations in CARD14, mutations in IL-36 receptor antagonist (IL-36RN) and adaptor-related protein complex 1 subunit sigma 3 (AP1S3) have also been identified to cause or contribute to pustular psoriasis that is a rare and severe form of psoriasis. IL-36Ra (encoded by IL-36RN) is released by keratinocytes and accumulates in the initial phase of psoriasis after inflammatory cytokines stimulation [ 32 ]. Loss of IL-36Ra in mice exacerbated IMQ-induced psoriasis-like dermatitis [ 33 ]. Mutations in IL36RN results in a reduced/loss of function of IL-36Ra and therefore enhances IL-36 and NF- κB signaling in keratinocytes [ 34 ]. AP1S3 is highly expressed in keratinocytes, with low expression in neutrophils or undetectable expression in CD4 + T cells. Mutations of AP1S3, such as p.Phe4Cys and p.Arg33Trp, are loss-of-function mutations and AP1S3 deficiency led to autoinflammation mediated by impaired keratinocyte autophagy and increased IL-36 signaling, finally contributing to the development of psoriasis [ 35 ].

Cytokines and receptors

Communication between immune cells and keratinocytes is through cytokines and their receptors, which plays a pivotal role in psoriasis pathogenesis. Mainly produced by immune cells, TNF-α, IFN-γ, IL-23/IL-17A, IL-22, etc, activate keratinocytes, triggering multiple cell signaling pathways, ultimately resulting in excessive keratinocytes proliferation and production of antimicrobial proteins, cytokines, chemokines, and growth factors. Among them, TNF-α, IL-17A, and IL-23 are of central importance in psoriasis as therapies targeting them are most efficient in the treatment of patients [ 10 ]. Recently, cytokines derived from or receptors expressed on keratinocytes have attracted more attention from researchers (Fig. 2 ).

Cytokines are essential in the pathogenesis of psoriasis. Recently, cytokines derived from or receptors expressed on keratinocytes have shown great importance in psoriasis. Keratinocytes are critical cytokine responders in psoriasis, as keratinocyte-specific deletion of their receptors (such as IL-17RA and IL-36R) alleviated psoriasiform lesion in psoriatic mouse model. Keratinocyte-derived IL-17C, IL-17E, IL-36, and IL-23 could induce expression of proliferative and proinflammatory genes by multiple signaling pathways, leading to epidermal hyperplasia and amplification of inflammation and leukocyte infiltration. IL-17RA IL-17 receptor A, TRAF6 TNF receptor-associated factor 6, IL-36R IL-36 receptor, IL-1RAcp IL-1 receptor accessory protein, TWEAK tumor necrosis factor (TNF)-like weak inducer of apoptosis, Fn14 factor-inducible 14, IL-22BP IL-22 binding protein.

The IL-23/IL-17 cytokine axis is considered as a major driver of psoriasis. IL-23 expressed by immune cells is believed to be required for the maintenance and expansion of IL-17-producing immune cells [ 10 ]. However, IL-23 is also produced by keratinocytes, but the role of keratinocyte-produced IL-23 in psoriasis is unclear. Recently, using a genetic mouse model, Li and colleagues showed that keratinocyte-derived IL-23 was sufficient to activate IL-17-producing immune cells to secrete IL-17 and cause a chronic skin inflammation. Further investigation found that epigenetic regulation by H3K9 dimethylation controled IL-23 expression in keratinocytes, which may contribute to psoriasis [ 36 ].

The IL-17 family cytokine contains six members: IL-17A (commonly referred to as IL-17), IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F, which acts through a IL-17 receptor heterodimer. IL-17A, the major downstream cytokine of IL-23, is most strongly implicated and well-studied in psoriasis pathogenesis [ 37 ]. Briefly, IL-17A binds to its receptors on keratinocytes, through multiple cell signaling pathways, it induces the production of keratinocyte-derived antimicrobial peptides (e.g. S100A7, LL37, and DEFB4A) to activate innate immunity, chemokines (e.g. CXCL1, CXCL8, and CCL20) to recruit leukocytes such as neutrophils, Th17 cells, mDCs and macrophage, and multiple pro-inflammatory genes (such as IL-1β, IL-6, IL-8, and TNF-α), thus amplifying the IL-23/IL-17A axis and producing the “feed forward” inflammatory circuits. On the other hand, IL-17A could indirectly induce epidermal hyperplasia via increased expression of IL-19 and IL-36 by keratinocytes [ 11 , 37 ]. However, there has been less attention on other IL-17 family members, despite of their upregulation in psoriatic lesions. Like IL-23, IL-17E (IL-25) is derived from both immune cells and keratinocytes, which was highly expressed in the epidermal layer of lesional skin of psoriatic patients and IMQ-induced psoriasis mouse model. IL-17E injection caused psoriasis-like pathology in mouse skin, whereas global knockout of IL-17E ameliorated IMQ-induced psoriasis. Specially, IL-17E deficiency in keratinocytes could lead to resistance to IMQ-induced psoriasis. Mechanically, epidermal IL-17E expression is upregulated by IL-17A in psoriasis, and through its receptor IL-17RB on keratinocytes, it promotes keratinocyte proliferation and production of inflammatory cytokines and chemokines via STAT3 activation [ 38 ]. IL-17C is another IL-17 family member that has been identified as an epithelial cytokine predominantly produced by keratinocytes in skin [ 38 ]. IL-17C is reported to be increased in keratinocytes in a number of inflammatory skin diseases, such as psoriasis and atopic dermatitis (AD) [ 39 ]. And keratinocyte-specific IL-17C transgenic mice developed a spontaneous psoriasis-like phenotype [ 40 ]. Using MOR106, a specific anti-IL-17C antibody, it attenuated keratinocyte hyperproliferation and skin inflammation in mouse models of psoriasis and AD [ 41 ]. Of note, IL-17C builds a self-amplifying circuit, which results in enhanced production of inflammatory cytokines, chemokines, and antimicrobial peptides by keratinocytes, ultimately recruiting immune cells to the skin. It is noteworthy that IL-17C is not a specific target for psoriasis and AD but for a variety of inflammatory skin diseases.

The IL-17 receptor family contains five members, including IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE. IL-17RA is the most common co-receptor subunit of IL-17A, IL-17C, IL-17E, and IL-17F. Recently, Moos and colleagues determined the critical cell type responding to IL-17 by using different murine models with IL-17RA deficient in distinct cell types, such as keratinocytes, T cells, neutrophils, and macrophages. They found that only IL-17RA deletion in keratinocytes significantly protected mice from IMQ-induced psoriasis-like dermatitis, which is similar to full-body deficiency of IL-17RA. Importantly, mice lacking IL-17RA in keratinocytes also featured significantly decreased expression of IL-1, IL-22, and CXCL2, as well as loss of neutrophil infiltration into the skin. However, deletion of IL-17RA in T cells, neutrophils or macrophages showed no impact on disease development [ 42 ]. Thus, keratinocytes are the crucial IL-17 responder in psoriasis.

The IL-36 family is a member of IL-1 superfamily and comprises three agonists (IL-36α, IL-36β, and IL-36γ) and one antagonist (IL-36 receptor antagonist (IL-36Ra)). All of the members bind to a heterodimeric receptor complexes composed of IL-36 receptor (IL-36R) and IL-1 receptor accessory protein (IL-1RAcp). Now, the IL-36 family cytokines are emerging as crucial players in the pathogenesis of psoriasis. Loss of IL-36Ra exacerbated IMQ-induced psoriasiform lesion [ 33 ]. By contrast, mice with IL-36α deficiency (but not IL-36β or IL-36γ deficiency), had significantly reduced psoriasis-like phenotype induced by IMQ [ 33 , 43 ]. Similarly, IL-36R deficiency protected mice from IMQ-induced psoriasis-like dermatitis [ 33 ]. Specially, conditional deletion of IL-36R in keratinocytes showed similar protection as global deficiency of IL-36R [ 44 ], suggesting keratinocyte is the primarily responsive cell type for IL-36 signaling in psoriasis. Notably, IL-36 exerts its pathogenic role by promoting keratinocyte proliferation and enhancing the production of inflammatory cytokines and chemokines to amplify psoriatic inflammation [ 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. Recently, therapies targeting IL-36 have been developed for psoriasis treatment, which are under clinical trials.

IL-22 is another major downstream cytokine of IL-23, which is mainly produced by CD4 + T cells and group 3 innate lymphoid cells (ILC3). Its receptor IL-22R is expressed on non-hematopoietic cells such as keratinocytes, epithelial cells, and hepatocytes [ 52 ]. IL-22 exerts its pathogenic role in psoriasis by inhibiting the terminal differentiation of keratinocytes, as well as inducing antimicrobial peptides and proinflammatory chemokines [ 53 ]. IL-22 binding protein (IL-22BP) is a natural inhibitor of IL-22 that specially binds to IL-22, thereby inhibiting its biological function. Both genetic IL-22BP deficiency and anti-IL-22BP neutralizing antibody exacerbated IMQ-induced psoriasis-like skin disease with increased levels of epidermal thickeness and enhanced expression of inflammatory cytokines and IL-22-inducible antimicrobial peptides. Further investigation found that IL-24 is a downstream target of IL-22, regulating the terminal differentiation of keratinocytes [ 54 ].

Except for TNF-α, another member of TNF superfamily, TNF-like weak inducer of apoptosis (TWEAK) has recently been identified as a key cytokine in psoriasis. Daniel and colleagues showed that TWEAK deficiency alleviated IMQ-induced psoriatic dermatitis [ 55 ]. In addition, mice deficient in fibroblast growth factor-inducible 14 (Fn14, the receptor for TWEAK) also reduced the disease severity [ 56 ]. Most recently, using a mouse model with keratinocyte-specific deletion of Fn14, Rinkesh and colleagues have demonstrated a central role of keratinocytes in the action of TWEAK in psoriasis. Loss of Fn14 in keratinocytes protected mice from IMQ-induced psoriasiform hyperplasia and inflammation. Importantly, blocking TWEAK showed a similar reduction in epidermal thickness, skin infiltrates, and inflammation mediators as blocking TNF-α and IL-17A. However, there was no further improvement with combined treatments [ 57 ]. Altogether, blocking TWEAK may be an alternative therapeutic strategy for psoriasis.

Metabolic mechanism

One of the hallmark of psoriasis is keratinocyte hyperproliferation, which requires extensive energy, amino acids, nucleotides and lipids. In recent years, emerging evidence has implicated that metabolism is essential in the pathogenesis of psoriasis, especially in keratinocytes.

Glucose is the main source of energy for all cells, particularly for rapidly proliferating cells. Now, glucose metabolism is being recognized as a key metabolic mechanism involved in psoriasis. Glucose uptake is through glucose transporters, and glucose transporter 1(Glut1) is most widely expressed and dramatically elevated in psoriatic epidermis from the patient and IMQ-induced psoriasis mouse model [ 58 , 59 ]. Keratinocyte-specific deletion of Glut1 did not affect normal skin development and homeostasis, but ameliorated IMQ- and IL-23-induced psoriasiform hyperplasia. Furthermore, topical application of GLUT inhibitor WZB117 attenuated both posriasiform hyperplasia and inflammation in mouse models of psoriasis, identifying glucose transport as a promising therapeutic target of psoriasis [ 59 ]. Also, suppressing glucose metabolism by 2-deoxy-d-glucose (2DG), a glucose analog, inhibited keratinocyte proliferation and alleviated IMQ-induced skin lesions [ 58 , 60 , 61 ]. Glycolysis and aerobic respiration are also related with keratinocyte function in psoriasis. Recently, a key rate-limiting enzyme of glycolysis, pyruvate kinase M2 (PKM2), was found significantly increased in the lesional skin of psoriatic patients and IMQ-induced psoriasis-like dermatitis. Overexpression of PKM2 increased keratinocyte glucose metabolism, whereas silencing or inhibition of PKM2 suppressed keratinocyte cell glycolysis and proliferation. Moreover, genetic deletion of PKM2 in keratinocytes or pharmacological inhibition of PKM2 markedly reduced psoriasis-like skin lesions induced by IMQ. Importantly, EGF may contribute to the induction of PKM2 in keratinocyte through ERK1/2 pathway [ 61 ].

In addition to glucose metabolism, glutamate metabolism has been reported to be abnormal in psoriasis. Multiple metabolomics analysis revealed an elevation of glutamate metabolism in patients with psoriasis, which is positively correlated with the Psoriasis Area Severity Index (PASI) score. Glutamate metabolism serves a crucial role in psoriasis, as it may facilitate the hyperproliferating keratinocytes to meet their high metabolic demand, such as ATP or biosynthetic procurers [ 62 , 63 , 64 , 65 ]. Recently, Xia and colleagues found that Glutaminase 1(GLS1)-mediated glutaminolysis was aberrantly activated in psoriasis patients, as indicated by elevated mRNA and protein levels in both immune cells and keratinocytes, contributing to the pathogenesis of psoriasis. In keratinocytes, induction of GLS1 was caused by IL-17A/MALT1/c-Jun axis, and enhanced cell proliferation and chemokine production, contributing to the development of psoriasis phenotype [ 66 ].

Emerging evidence also suggests the importance of lipid metabolism in psoriasis. Studies analyzing plasma or serum showed altered lipid metabolites in psoriatic patients [ 67 , 68 ]. In psoriatic skin lesions, lipid metabolism abnormalities were also observed [ 69 , 70 ]. And our high-throughput transcriptome analysis of psoriatic skins identified notable differences in genes involved in lipid metabolism [ 71 ]. Sphingosine-1-phosphate (S1P), a metabolic product of sphingolipids, has been reported to be elevated in patients with psoriasis. It is a bioactivator that acts both as an intracellular second messenger and an extracellular ligand for G-protein-coupled receptors, which is involved in diverse cellular processes, including immune cell trafficking and keratinocyte proliferation and differentiation [ 72 , 73 ]. To date, the role of S1P in psoriasis is controversial. Schaper and colleagues found that topical application of S1P alleviated IMQ-induced epidermal thickening and skin inflammation in the ear [ 74 ]. And using a selective S1P1 receptor agonist- Sy1930, it attenuated propranolol-induced psoriasis in pigs [ 75 ]. Furthermore, Jeon and colleagues showed that elevating S1P by inhibiting of S1P lyase ameliorated IMQ-induced psoriasis-like dermatitis, and reduced IL-17- and IL-22-induced cell proliferation and promoted keratinocyte differentiation [ 76 ]. However, blocking S1P generation by ceramidase inhibitor or sphingosine kinase 1/2 inhibitor protected mice from IMQ- induced skin lesions and inflammation, especially through inhibiting Th17 cell differentiation. Thus, it would be better to use conditional knockout mice to study the role of S1P in psoriasis, to dissect its role in immune cells and keratinocytes. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a chaperone protein to the low-density lipoprotein (LDL) receptors, which promotes the degradation of LDL receptors. Induction of PCSK9 was observed in the lesional skin of both psoriatic patients and IMQ-induced psoriasis mouse model. Genetic deletion of PCSK9 or topical application of siRNA targeting PCSK9 relieved the psoriasis-like inflammation as well as the proliferation of keratinocytes. Notably, silencing PCSK9 in keratinocytes induced cell apoptosis and inhibited hyperproliferation [ 77 ].

Cellular metabolism in keratinocytes not only affects the supply of energy for keratinocyte proliferation but is also involved in a variety of inflammatory and immune response.

Cell signaling

The signaling pathway is a major regulator of psoriasis involved in diverse biological aspects we discussed in this review, which influences both immune cells and keratinocytes. Major signaling pathways altered in psoriasis include signal transducer and activator of transcription (STAT), nuclear factor-kappa B (NF-κB), MAPK, etc. In this section, only the key regulators of major signaling pathways in keratinocytes will be discussed and other factors involved in cell signaling may be discussed in other sections.

STAT signaling pathways

The JAK (Janus kinase)/STAT signaling is known to play an essential role in psoriasis. Of note, among the various STATs, STAT3 is hyperactivated in both immune cells and keratinocytes, regulating cell proliferation, differentiation, and apoptosis. In keratinocytes, STAT3 has a central role in response to various inflammatory cytokines in psoriasis, such as IL-6, IL-17, IL-21, IL-19, IL-22, etc. STAT3 activation in keratinocytes inhibited cell differentiation, promoted proliferation and production of antimicrobial peptides [ 78 , 79 ]. The transgenic mouse model overexpressing STAT3 in keratinocytes led to the spontaneous development of psoriasis-like lesions with similar cytokine profiles as those of human psoriatic plaques [ 80 , 81 ]. Moreover, specific deletion of STAT3 in keratinocytes rather than in T cells reduced psoriasis-like dermatitis [ 82 ]. Thus, STAT3 in keratinocytes is more important for the development of psoriasis.

NF-κB signaling pathway

Increasing evidence has shown that NF-κB signaling contributes to the pathogenesis of psoriasis by acting on immune cells and keratinocytes. NF-κB was highly activated in the lesional skin of psoriatic patients [ 83 ]. Using different mouse models, Bernd and colleagues showed that aberrant activation of NF-κB in both keratinocytes and T cells are important for the development of inflammatory skin diseases, like psoriasis. Mice with global deletion of IκBα developed psoriasis-like skin symptoms, while IκBα deficiency in keratinocytes only resulted in epidermal hyperplasia without epidermal inflammation. However, loss of IκBα in both keratinocytes and T cells led to a similar phenotype as that in global deficiency. Moreover, keratinocyte-specific deletion of RelA rescued the phenotype developed in global IκBα knockout mice [ 84 ]. And mice deficient in NF-κB alleviated IMQ-induced psoriasis-like dermatitis [ 85 ]. These indicate NF-κB activation in both keratinocytes and immune cells are essential for the development of psoriasis.

MAPK signaling pathway

MAPK kinases are involved in the pathogenesis of psoriasis, and play important roles in regulating keratinocyte proliferation and immune response. p38 was activated in psoriatic epidermis and cutaneous activation of p38 resulted in psoriasis-like dermatitis in mice. Topical application of p38 inhibitor attenuated IMQ-induced dermatitis [ 86 ]. In vitro studies showed that p38 inhibitor suppressed TNF-α or IL-17A-stimulated inflammatory response in keratinocytes [ 86 , 87 ]. Like p38, ERK1/2 was also activated in the epidermis of psoriatic patients [ 88 ]. Inhibition of ERK by a specific ERK inhibitor JSI287 decreased IMQ-induced psoriasiform lesion [ 89 ]. DUSP1/MKP-1, a member of the dual-specificity phosphatase family, acts as a negative regulator of MAPK pathway. It was significantly downregulated in psoriasis patients and overexpression of DUSP1 markedly inhibited keratinocyte proliferation and promoted apoptosis by targeting ERK/Elk-1/Egr-1 signaling pathway [ 90 ].

Other signaling pathways

Secreted frizzled-related protein (SFRP) 4, a negative regulator of Wnt, is pivotal for epidermal hyperplasia. SFRP4 was decreased in the skin epidermis of psoriatic patients and mouse models of psoriasis by an epigenetic regulation- DNA methylation. SFRP4 treatment or Wnt inhibition suppressed keratinocyte hyperproliferation induced by IL-6 in vitro. Administration of SFRP4 or pharmacological inhibition of Wnt alleviated psoriasis-like dermatitis induced by IMQ [ 91 ]. Recently, Hippo-Yes-associated protein (YAP) signaling has been reported to be involved in psoriasis. YAP and its downstream target amphiregulin (AREG) were dramatically induced in skin of psoriatic patients and in psoriasis-like mouse model. As an oncogene, YAP promotes cell proliferation and inhibits cell apoptosis. And silencing YAP inhibited keratinocyte proliferation, induced cell cycle arrest, and promoted cell apoptosis, which acts through an AREG-dependent pathway [ 92 ].

Transcription factor

Except for the transcription factors involved in the major signaling pathways in psoriasis discussed above, some other transcription factors expressed in keratinocytes have emerged as important regulators in psoriasis, which have appealing therapeutic potential.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a critical role in regulating cellular defenses against oxidative or toxic stresses. In psoriasis, Nrf2 was highly expressed and activated in psoriatic epidermis. Overexpression of Nrf2 facilitated keratinocyte proliferation by increasing the expression of hyperproliferation-associated keratins, including keratin (KRT) 6, KRT16, and KRT17. Locally silencing Nrf2 reduced IMQ-induced psoriasis-like dermatitis and inhibited KRT6, KRT16, and KRT17 expression [ 93 ]. These indicate Nrf2 acts as a regulator of hyperproliferation-associated keratins, which is a potential therapeutic target for psoriasis. AP-1 transcription factor superfamily (including JUN, JUNB, JUND, FOS, FOSB, FRA1, and FRA2) is essential in the pathogenesis of psoriasis. Epidermal deletion of c-Jun and JunB led to a spontaneous psoriasiform phenotype [ 94 ]. FRA1 was evidently elevated in the lesional skin of psoriatic patients. Overexpression of FRA1 in keratinocytes triggerred enhanced production of proinflammatory cytokine and chemokine and promoted keratinocyte migration and wound healing process [ 95 ]. Grainyhead-like 3 (GRHL3) is a transcription factor that plays a critical role in epidermal differentiation and barrier formation. Upregulation of GRHL3 was observed in the epidermis of both psoriatic patients and IMQ-induced psoriasis mouse model. GRHL3 deficiency in keratinocytes aggravated IMQ-induced psoriasiform phenotype [ 96 ]. Further investigation identified thymus and activation-regulated chemokine (TARC) as a downstream of GRHL3 that promoted keratinocyte proliferation after loss of GRHL3 [ 97 ].

Non-coding RNAs

Besides genetic factors, epigenetic regulation is also involved in psoriasis. Non-coding RNA regulation is one of the epigenetic regulations important for various biological processes and disease pathogenesis. The role of non-coding RNAs in psoriasis, especially the role of microRNAs has been extensively explored previously [ 98 , 99 ]. Here, we will focus on the effects of non-coding RNAs (microRNA and long non-coding RNA (lncRNA)) on keratinocytes in psoriasis.

Role of microRNAs in psoriatic keratinocytes

MicroRNAs are short non-coding RNAs, which inhibit protein-coding gene expression at the post-transcriptional level and their dysfunction is linked to psoriasis [ 100 ]. Early studies observed that more than 250 microRNAs were aberrantly expressed in the lesional skin of psoriatic patients, and play an essential role in modulating the functions of multiple cell types important for psoriasis pathogenesis, such as keratinocytes and leukocytes, as well as the interplay between them [ 98 , 101 ]. Here, we will discuss how microRNAs affect psoriatic keratinocytes and psoriasis, and the summary of microRNAs involved in keratinocytes is shown in Table 2 .

Some microRNAs show aberrant upregulation in psoriasis and mainly promote keratinocyte proliferation. For example, microRNA (miR)-31 is upregulated in psoriatic skin of patients or IMQ-induced mouse model, especially in the basal or superbasal cell layers of epidermis. Genetic deletion of miR-31 in keratinocytes alleviated psoriasiform hyperplasia and inflammation induced by IMQ or IL-23. Of note, miR-31 was induced by NF-κB, which in turn suppressed protein phosphatase 6 (ppp6c), and thereby promoted the G1 to S phase progression, finally resulting in increased proliferation of keratinocytes in psoriasis [ 102 ]. miR-17-92 cluster, including miR-17, miR-18a, miR-19a, miR-19b miR-20a, and miR-92a, was also induced in psoriatic lesions and positively correlated with PASI. Zhang and colleagues found that STAT1-induced miR-17-92 cluster promoted keratinocyte proliferation by suppressing cyclin-dependent kinase inhibitor 2B (CDKN2B) and increased the chemokine production via inhibition of suppressor of cytokine signaling 1 (SOCS1), suggesting miR-17-92 as a potential therapeutic target for psoriasis [ 103 ]. Moreover, miR-130a, highly expressed in psoriatic lesions, directly targeted serine/threonine kinase 40 (STK40) to activate NF-κB pathway or indirectly upregulated sex-determining region Y chromosome-box 9 (SOX9) to activate JNK/MAPK pathway, thus promoting keratinocytes viability and migration and inhibiting apoptosis of keratinocytes [ 104 ]. In addition, miR-223 targeted phosphatase and tensin homolog (PTEN), a tumor suppressor inhibiting the PI3K/AKT signaling pathway, and ultimately contributed to increased proliferation and decreased apoptosis in IL-22-stimulated HaCaT cells [ 105 ]. However, miR-146a/b, which were highly expressed in the psoriatic skin lesions, negatively regulated keratinocyte proliferation and played protective roles in psoriasis. miR-146a targeted TNF receptor-associated factor 6 (TRAF6) and epidermal growth factor receptor (EGFR), which regulated keratinocyte proliferation and inflammatory responses [ 106 , 107 ]. Overexpression of miR-146a inhibited epidermal proliferation, impaired neutrophil infiltration, and suppressed IL-17-driven psoriatic inflammation of mouse models via its target genes, while genetic deficiency in miR-146a exacerbated pathology of psoriasis-like skin inflammation especially in the early onset of the disease [ 101 ]. miR-146b facilitated miRNA-146a to inhibit the proliferation and psoriasis-related target gene expression (such as FERM domain containing kindlin 1 (FERMT1), NUMB endocytic adaptor protein (NUMB), etc.) in cultured human keratinocytes stimulated with IFN-γ or TNF-α [ 108 ].

Besides, some microRNAs are aberrantly downregulated in psoriatic skin lesions and exert proliferation-inhibiting and differentiation-promoting effects on keratinocytes. miR-let-7b, the first known human microRNA, was dramatically reduced in psoriatic epidermis of IMQ-induced psoriasis mouse model. Using a keratinocyte-specific miR-let-7b transgenic mouse model, Wu and colleagues showed that overexpression of miR-let-7b in keratinocytes ameliorated psoriasis-like dermatitis induced by IMQ. Mechanically, miR-let-7b inhibited ERK signaling pathway through targeting IL-6, resulting in the acceleration of keratinocyte differentiation in psoriasis [ 109 ]. Downregulation of miR-145-5p was observed in the lesional skin of psoriatic patients. Overexpression of miR-145-5p inhibited cell proliferation and chemokine production by targeting mixed-lineage kinase 3 (MLK3)-mediated NF-κB and STAT3 activation in vitro and alleviated psoriasiform hyperplasia and inflammation in vivo. By contrast, inhibition of miR-145-5p led to the opposite effects [ 110 ]. Similarly, overexpression of miR-187 suppressed keratinocyte hyperproliferation and protected mice from IMQ-induced skin lesions through inhibition of CD276-STAT3 signaling [ 111 ]. miR-486-3p was markedly decreased in the epidermis of psoriatic patients and showed a negative correlation with the disease severity. TGFβ/SMAD was identified as an upstream of miR-486-3p. In psoriasis, inactivation of TGFβ/SMAD pathway led to the loss of miR-486-3p, resulting in KRT17 (a cytoskeletal protein that play a pathogenic role in psoriasis) overexpression and keratinocyte hyperproliferation [ 112 ]. In line with miR-486-3p, miR-138 is another negative regulator of KRT17 by targeting human telomerase reverse transcriptase (hTERT), subsequently inhibiting keratinocyte proliferation and increasing cell apoptosis [ 113 ]. Moreover, miR-125b-5p and miR-181b-5p shared the same target gene AKT3, which at least partly contributed to the inhibition of keratinocyte proliferation in psoriasis [ 114 ]. Besides, miR-125b-5p and miR-181b-5p may suppress keratinocyte proliferation by targeting fibroblast growth factor receptor 2 (FGFR2) and ubiquitin-specific peptidase 2 (USP2) or TLR4, respectively [ 115 , 116 ]. Furthermore, miR-20a-3p and miR-330 are two IL-22 responsive microRNAs identified in psoriasis. miR-20-3p promoted keratinocyte cell apoptosis and inhibited cell proliferation by Scm like with four mbt domains 1 (SFMBT1) and subsequent TGF-β1/Survivin pathway [ 117 ]. miR-330 can directly target catenin beta 1 (CTNNB1, also known as β-catenin), leading to repression of CyclinD1 and Axin2 and subsequent suppression of keratinocyte proliferation [ 118 ]. Importantly, miR-876-5p suppressed PI3K/AKT and ERK signaling way to regulate keratinocyte proliferation by targeting Angiopoietin-1 (Ang-1) [ 119 ]. Additionally, as a well-known tumor suppressor, miR-217 targeted Grainyhead-like 2 (GRHL2), a developmental transcriptional factor with ability of influencing epithelial barrier function and keratinocyte differentiation, to inhibit keratinocyte proliferation and promote cell differentiation [ 120 ].

MicroRNAs play crucial roles in psoriasis, particularly modulating keratinocyte proliferation, differentiation, apoptosis, and inflammation. With all those important signaling pathways involved, microRNAs demonstrate such a comprehensive and potent role in the pathogenesis of psoriasis (Fig. 3 ).

Non-coding RNAs play pivotal roles in the pathogenesis of psoriasis. In keratinocytes, they can affect cell proliferation, apoptosis, differentiation, and inflammatory response through targeting multiple signaling pathways, such as NF-κB signaling, STAT3 signaling, ERK signaling, AKT signaling, etc. Also, expression of some of microRNAs are found to be regulated by NF-κB, STAT, or TGFβ signaling. MEG3 maternally expressed gene 3, ppp6c protein phosphatase 6, STK40 serine/threonine kinase 40, MLK3 mixed-lineage kinase 3, SFMBT1 Scm like with four mbt domains 1, PTEN phosphatase and tensin homolog, Ang1 Angiopoietin-1, CDKN2B cyclin-dependent kinase inhibitor 2B, SOCS1 suppressor of cytokine signaling 1, K17 keratin 17.

Role of lncRNAs in psoriatic keratinocytes

Unlike microRNAs, lncRNAs are a group of non-protein coding transcripts >200 nucleotides and regulate gene expression at both transcriptional and post-transcriptional levels [ 121 ]. Increasing evidence has shown that lncRNAs are involved in the pathogenesis of psoriasis, affecting the function of keratinocytes, T cells and dendritic cells. In this review, we are specially focusing on the role of lncRNAs in keratinocytes.

Psoriasis-associated non-protein coding RNA induced by stress (PRINS), the first identified psoriasis susceptibility-associated lncRNA, was highly expressed in the epidermis of non-lesional and lesional skin of psoriatic patients. PRINS was induced in response to the stress, and silencing of it decreased keratinocyte viability under stress condition [ 122 ]. Further investigation identified G1P3 as a downstream target of PRINS, which was also upregulated in psoriatic epidermis and exerted anti-apoptotic effects in keratinocytes [ 123 ]. Besides, lncRNA-MSX2P1 was elevated in the lesional skin of psoriatic patients and IL-22-stimulated keratinocytes. It accelerated IL-22-induced keratinocyte proliferation and inhibited apoptosis by inhibition of miR-6731-5p and activation of S100A7 [ 124 ]. Similarly, upregulation of lncRNA RP6-65G23.1 has been found in psoriatic epidermis [ 125 ]. Overexpression of RP6-65G23.1 promoted keratinocyte proliferation and decreased cell apoptosis, whereas silencing of it showed opposite effects. Of note, RP6-65G23.1 regulated keratinocyte proliferation via AKT and ERK1/2 pathways, and affected keratinocyte apoptosis by Bcl2 and Bcl-xl [ 121 ]. In contrast, lncRNA maternally expressed gene 3 (MEG3) was markedly downregulated in psoriatic skin. MEG3 suppressed keratinocyte proliferation and accelerated cell apoptosis by targeting miR-21 and increasing the expression of Caspase 8 [ 126 ]. Furthermore, MEG3 inhibited keratinocyte inflammatory response and enhanced autophagy via PI3K/AKT/mTOR signaling pathway in vitro or in vivo [ 127 ].

Therefore, lncRNAs influence the proliferation, apoptosis and inflammatory responses of keratinocytes in psoriasis. Identifying dysregulated lncRNAs and the related networks involved in psoriasis will be an important area of research and would provide potential new clues for future diagnosis and treatment of this disease.

Antimicrobial peptides

Antimicrobial peptides, including LL37, β-defensins and S100 proteins are small proteins that activate innate immune response and are associated with psoriasis pathogenesis [ 128 ]. Studied found antimicrobial peptides could also regulate the function of keratinocytes. S100A7 is an antimicrobial peptide that is stored in differentiated keratinocytes and S100A7 was significantly elevated in psoriasis patients. Studies suggest that S100A7 expression can be induced by differentiation of keratinocytes dependent on protein kinase C pathway or downregulation of Caspase 8. However, overexpression of S100A7 led to aberrant keratinocyte differentiation in psoriasis [ 129 , 130 , 131 ], suggesting a negative feedback during psoriasis development. Furthermore, C10orf99 is another antimicrobial peptide identified recently that was highly expressed in psoriatic epidermis of patients or IMQ-induced mouse model. Topical application of C10orf99 shRNA effectively attenuated IMQ-induced psoriasis-like dermatitis. Notably, C10orf99 promoted keratinocyte proliferation by enhancing the G1/S transition and activating the ERK1/2 and NF-κB pathways, thus contributing to psoriasis pathogenesis [ 132 ]. Therefore, antimicrobial peptides exert important impacts on psoriatic keratinocytes.

Proteins with other functions

Proteins upregulated in psoriasis.

Emerging evidence has shown that the ubiquitin-proteasome system plays a crucial role in the pathogenesis of psoriasis. Zieba and colleagues showed that the proteasome assembly chaperone POMP (proteasome maturation protein) was upregulated in psoriatic skin, resulting in an increase of proteasome levels and activities. Silencing POMP inhibited cell proliferation and differentiation, and promoted cell apoptosis via inhibition of the proteasome assembly [ 133 ]. E3 Ligase tripartite motif-containing 21 (Trim21) belongs to the Trim protein family with E3 ligase activity. In psoriatic epidermis, Trim21 was found overexpressed and induced activation of STAT3 through ubiquitylating and stabilizing KRT17 in keratinocytes, thus promoting the development of psoriasis [ 134 ]. Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) is another E3 ligase that was downregulated in psoriatic epidermis. Suppression of NEDD4L promoted keratinocyte hyperplasia by mediating GP130 degradation and activation of STAT3 [ 135 ]. TRAF6 is a signaling adaptor and E3 ubiquitin ligase. In psoriasis, IL-17 signals through TRAF6, then activates NF-κB and MAPK pathways. Keratinocyte-specific deletion of TRAF6 diminished psoriasiform hyperplasia and IL-17-mediated inflammation [ 136 ]. Prokineticin 2 (PK2), a neuroendocrine peptide, is a psoriasis-specific factor highly expressed psoriatic skins. PK2 enhanced the production of IL-1 in keratinocytes and macrophages, thus inducing keratinocyte hyperproliferation and inflammatory cascades in psoriasis. Overexpression of PK2 exacerbated psoriasis-like dermatitis in mice, whereas knockdown of PK2 ameliorated psoriasis-like dermatitis [ 137 ]. Therefore, PK2 could be a novel psoriasis-specific target in the treatment of psoriasis. Ras-related C3 botulinum toxin substrate 1 (RAC1) belongs to the small GTPases of the Rho family. RAC1 was hyperactivated in psoriatic epidermis and overexpression of RAC1 in keratinocytes caused psoriasis-like skin lesions in mice. Epidermal activation of RAC1 stimulated a variety of key signaling pathways, such as STAT3, ZNF750, and NF-κB, leading to keratinocyte hyperproliferation and cytokines production, as well as cell differentiation inhibition [ 138 ]. Plexin-B2, an axon-guidance molecule, was found greatly increased in keratinocytes of psoriatic patients and IMQ-induced psoriatic mouse model. Silencing Plexin-B2 decreased IMQ-induced psoriatic dermatitis. Mechanically, binding by its ligand CD100, Plexin-B2 promoted the production of inflammatory chemokines/cytokines and the formation of the NLRP inflammasome in keratinocytes through activating NF-κB pathway, subsequently strengthening inflammatory responses of keratinocytes in psoriasis [ 139 ]. CCN1, also known as cysteine-rich protein 61 (Cyr61), is an extracellular protein elevated in psoriatic lesions. It stimulated keratinocyte proliferation and a variety of immune-related molecule expression by keratinocytes, such as IL-8, IL1-β, CCL20, HLA-ABC, HLA-DR, and ICAM. Silencing or blocking CCN1 alleviated IL-23- or IMQ-induced psoriasis-like dermatitis [ 140 , 141 , 142 , 143 ]. High-mobility group protein B1 (HMGB1) is a nuclear protein that can be released to act as a cytokine when cells undergo stress. In psoriasis, HMGB1 can be released from keratinocytes, which potentiates the production and secretion of IL-18 by keratinocytes through an autocrine mechanism. Importantly, blocking HMGB1 or IL-8 by neutralizing antibodies not only attenuated but also accelerated the recovery from psoriasis-like dermatitis induced by IMQ [ 144 ]. Recently, a member of the epidermal differentiation complex, Cornulin (CRNN), was shown highly expressed in psoriatic epidermis from patients or IMQ-induced mouse model. Induction of CRNN in keratinocytes activated PI3K/AKT pathway, contributing to keratinocyte hyperproliferation [ 145 ].

Proteins downregulated in psoriasis

Galectin-3, which belongs to the galectin family of β-galactoside-binding lectins, is a psoriasis-specific protein downregulated in psoriatic epidermis. Galectin-3 deficient in epidermal keratinocytes resulted in a spontaneous development of psoriasis-like phenotype. Administration of recombinant Galectin-3 ameliorated IMQ-induced psoriasis-like dermatitis. Notably, downregulation of Galectin-3 altered keratinocyte differentiation and apoptosis and induced the expression of antimicrobial peptides (S100A7, S100A8, and S100A9) and chemokines (CXCL1, CXCL8, and CCL20) by activation of JNK signaling, leading to neutrophil accumulation [ 146 ]. Cholecystokinin octapeptide (CCK8), a stimulatory hormone released from enteroendocrine I-cells of the intestine, was constitutively expressed in the epidermis of normal skin, but decreased in psoriatic patients. Administration of sulfated CCK8 ameliorated IMQ-induced psoriasiform hyperplasia and inflammation through an autocrine or paracrine manner with decreased expression of IL-17, IL-22, and IL-6 but not IL-23. In vitro studies found that IL-17 stimulation reduced CCK8 expression, which may lead to the induction of IL-6 [ 147 ]. Connexin 43 (Cx43) is a member of gap junction protein, which is abundantly expressed in epidermis. Cx43 was markedly downregulated in psoriatic epidermis and IL-22-stimulated keratinocyte. Downregulation of Cx43 significantly promoted cell proliferation and decreased gap junction intercellular communication in keratinocytes, resulting from IL-22-induced JNK pathway activation [ 148 ].

Concluding remarks

In this review, we have highlighted the critical roles of keratinocytes in psoriasis. Keratinocytes participate in both the initiation and maintenance phases of psoriasis. There are various factors that can regulate keratinocytes, including genetic regulation, cytokines and receptors, metabolism, cell signaling, transcription factors, non-coding RNAs, antimicrobial peptides, and proteins with other different functions. These modulating factors are not independent, but work together to alter the biological behavior of keratinocytes via multiple mechanisms, linking keratinocytes with psoriasis.

Although our understanding of the role of keratinocytes in psoriatic pathogenesis has advanced considerably, our knowledge about how various factors regulate the detailed functions of keratinocytes are still limited. Right now, many anti-psoriatic drugs, especially the biologics have demonstrated good efficacy, however, long-term efficacy and safety are still the problems for psoriasis treatment. Therefore, it is of great need to discover better treatment targeting keratinocytes more selectively and efficiently. Investigation into the mechanisms of keratinocyte-immune cell interaction network may shed light on restoring keratinocyte homeostasis and benefiting the alleviation of psoriasis.

Data availability

All data generated during and/or analyzed during the current study are available.

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Acknowledgements

This work was sponsored by grants from National Natural Science Foundation of China (No. 81900612, 81872522, 82073429 and 82103712), Innovation Program of Shanghai Municipal Education Commission (No.2019-01-07-00-07-E00046), Clinical Research Plan of SHDC (No. SHDC2020CR1014B, SHDC12018X06), Program of Shanghai Academic Research Leader (No. 20XD1403300), and Research Program of Shanghai Skin Disease Hospital (No. 2019KYQD08).

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Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, 200443, Shanghai, China

Xue Zhou, Youdong Chen, Lian Cui, Yuling Shi & Chunyuan Guo

Institute of Psoriasis, Tongji University School of Medicine, 200443, Shanghai, China

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XZ. organized literature and wrote the manuscript; YC. organized literature and wrote the manuscript; LC. revised the manuscript and checked some important information; YS. instructed the structure and revision of the manuscript; CG. provided the idea of this manuscript and revised the manuscript. All authors read and approved the final paper.

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Zhou, X., Chen, Y., Cui, L. et al. Advances in the pathogenesis of psoriasis: from keratinocyte perspective. Cell Death Dis 13 , 81 (2022). https://doi.org/10.1038/s41419-022-04523-3

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New drug is gamechanger in psoriasis treatment

A novel drug almost entirely cleared moderate to severe psoriasis in over 60% of the patients who took part in two phase three clinical trials of a new drug.

The University of Manchester and Salford Royal NHS Foundation Trust led studies on Bimekizumab , both published in the prestigious New England Journal of Medicine today, were funded by UCB Pharma; the company that developed the treatment which could be available in as little as 12 months.

Given as an injection under the skin, Bimekizumab is a monoclonal antibody and the first to block both Interleukin 17A and Interleukin 17F which are overexpressed in psoriasis .

Interleukin 17A and Interleukin 17F are two types of special proteins called cytokines which regulate the immune system. Other psoriasis drugs have only been able to block 17A.

One trial called BE RADIANT, compared the drug with Secukinumab, an IL17 A blocker: 743 patients were enrolled and 373 patients were assigned to Bimekizumab

The BE SURE trial compared Bimekizumab with Adalimumab : of the 478 patients enrolled, 319 patients were assigned to Bimekizumab.

Bimekizumab in both studies was given every 4 weeks for 16 weeks after which two maintenance schedules were possible: continue at every 4 weeks or go to an 8-week schedule .

Secukinumab and Adalimumab were given as per label.

The team assessed the efficacy of the treatments using the Psoriasis Area Severity Index (PASI) with PASI 100 indicating clear skin.

These trials show that Bimekizumab offers much hope to patients with moderate to severe psoriasis.. The higher rates of skin clearance under Bimekizumab compared with Secukinumab and Adalimumab were very impressive

At week 16 in the BE RADIANT trial, 230 patients (61.7%) on Bimekizumab reached complete skin clearance (PASI 100) whereas only 181 (48.9%) on Secukinumab achieved the same result.

At week 16 in the BE SURE trial, 275 or 86.2% of the patients on Bimekizumab achieved a PASI 90, one of the primary endpoints of the study where only 75 of the patients on Adalimumab-(47.2%) had the same result.

After approximately a year, there was no difference in outcomes for patients receiving B imekizumab every 4 weeks, or every 8 weeks.

Side effects were rare, though oral candidiasis- usually an easily treatable mouth infection - occurred in some patients.

Professor Richard Warren from The University of Manchester is also a Consultant Dermatologist at Salford Royal NHS Foundation Trust.

He has been leading some parts of the Bimekizumab development programme over the last 5 years as well as working with others on the design of the phase 3 programmes.

He said: “These trials show that Bimekizumab offers much hope to patients with moderate to severe psoriasis .

“The higher rates of skin clearance under Bimekizumab compared with Secukinumab and Adalimumab were very impressive.

“This drug sets a new bar for psoriasis treatment and we are hopeful that trials in treating other diseases triggered by over active Interleukin 17A and Interleukin 17F will also lead to improvements in patient care .”

The papers Bimekizumab versus Adalimumab in Plaque Psoriasis and Bimekizumab versus Secukinumab in Plaque Psoriasis are published in New England Journal of Medicine

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Psoriasis Pathogenesis and Treatment

Research on psoriasis pathogenesis has largely increased knowledge on skin biology in general. In the past 15 years, breakthroughs in the understanding of the pathogenesis of psoriasis have been translated into targeted and highly effective therapies providing fundamental insights into the pathogenesis of chronic inflammatory diseases with a dominant IL-23/Th17 axis. This review discusses the mechanisms involved in the initiation and development of the disease, as well as the therapeutic options that have arisen from the dissection of the inflammatory psoriatic pathways. Our discussion begins by addressing the inflammatory pathways and key cell types initiating and perpetuating psoriatic inflammation. Next, we describe the role of genetics, associated epigenetic mechanisms, and the interaction of the skin flora in the pathophysiology of psoriasis. Finally, we include a comprehensive review of well-established widely available therapies and novel targeted drugs.

1. Definition and Epidemiology

Psoriasis is a chronic inflammatory skin disease with a strong genetic predisposition and autoimmune pathogenic traits. The worldwide prevalence is about 2%, but varies according to regions [ 1 ]. It shows a lower prevalence in Asian and some African populations, and up to 11% in Caucasian and Scandinavian populations [ 2 , 3 , 4 , 5 ].

1.1. Clinical Classification

The dermatologic manifestations of psoriasis are varied; psoriasis vulgaris is also called plaque-type psoriasis, and is the most prevalent type. The terms psoriasis and psoriasis vulgaris are used interchangeably in the scientific literature; nonetheless, there are important distinctions among the different clinical subtypes (See Figure 1 ).

Clinical manifestations of psoriasis. ( A , B ) Psoriasis vulgaris presents with erythematous scaly plaques on the trunk and extensor surfaces of the limbs. ( C ) Generalized pustular psoriasis. ( D ) Pustular psoriasis localized to the soles of the feet. This variant typically affects the palms of the hands as well; hence, psoriasis pustulosa palmoplantaris. ( E , F ) Inverse psoriasis affects the folds of the skin (i.e., axillary, intergluteal, inframammary, and genital involvement).

1.2. Psoriasis Vulgaris

About 90% of psoriasis cases correspond to chronic plaque-type psoriasis. The classical clinical manifestations are sharply demarcated, erythematous, pruritic plaques covered in silvery scales. The plaques can coalesce and cover large areas of skin. Common locations include the trunk, the extensor surfaces of the limbs, and the scalp [ 6 , 7 ].

1.3. Inverse Psoriasis

Also called flexural psoriasis, inverse psoriasis affects intertriginous locations, and is characterized clinically by slightly erosive erythematous plaques and patches.

1.4. Guttate Psoriasis

Guttate psoriasis is a variant with an acute onset of small erythematous plaques. It usually affects children or adolescents, and is often triggered by group-A streptococcal infections of tonsils. About one-third of patients with guttate psoriasis will develop plaque psoriasis throughout their adult life [ 8 , 9 ].

1.5. Pustular psoriasis

Pustular psoriasis is characterized by multiple, coalescing sterile pustules. Pustular psoriasis can be localized or generalized. Two distinct localized phenotypes have been described: psoriasis pustulosa palmoplantaris (PPP) and acrodermatitis continua of Hallopeau. Both of them affect the hands and feet; PPP is restricted to the palms and soles, and ACS is more distally located at the tips of fingers and toes, and affects the nail apparatus. Generalized pustular psoriasis presents with an acute and rapidly progressive course characterized by diffuse redness and subcorneal pustules, and is often accompanied by systemic symptoms [ 10 ].

Erythrodermic psoriasis is an acute condition in which over 90% of the total body surface is erythematous and inflamed. Erythroderma can develop on any kind of psoriasis type, and requires emergency treatment ( Figure 2 ).

Erythrodermic psoriasis.

1.6. Comorbidities in Psoriasis

Psoriasis typically affects the skin, but may also affect the joints, and has been associated with a number of diseases. Inflammation is not limited to the psoriatic skin, and has been shown to affect different organ systems. Thus, it has been postulated that psoriasis is a systemic entity rather than a solely dermatological disease. When compared to control subjects, psoriasis patients exhibit increased hyperlipidemia, hypertension, coronary artery disease, type 2 diabetes, and increased body mass index. The metabolic syndrome, which comprises the aforementioned conditions in a single patient, was two times more frequent in psoriasis patients [ 11 , 12 ]. Coronary plaques are also twice as common in psoriasis patients when compared to control subjects [ 13 ]. Several large studies have shown a higher prevalence of diabetes and cardiovascular disease correlating with the severity of psoriasis [ 14 , 15 , 16 , 17 , 18 ]. There are divided opinions regarding the contribution of psoriasis as an independent cardiovascular risk factor [ 19 , 20 ]; however, the collective evidence supports that psoriasis independently increases risk for myocardial infarction, stroke, and death due to cardiovascular disease (CVD) [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. In addition, the risk was found to apply also to patients with mild psoriasis to a lower extent [ 21 , 27 ].

Vascular inflammation assessed via 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) found psoriasis duration to be a negative predicting factor. It was suggested that the cumulative effects of low-grade chronic inflammation might accelerate vascular disease development [ 29 ]. In a study by Metha et al., systemic and vascular inflammation in six patients with moderate to severe psoriasis was quantified by FDG-PET/CT. Inflammation foci were registered as expected in the skin, joints, and tendons. In addition, FDG uptake in the liver and aorta revealed subclinical systemic inflammation [ 30 ]. Furthermore, standardized uptake values were reduced in the liver, spleen, and aorta following treatment with ustekinumab {Kim, 2018 #359}. A new biomarker to assess CVD risk in psoriasis patients was proposed by nuclear magnetic resonance spectroscopy [ 31 ]. The signal originating from glycan N-acetylglucosamine residues called GlycA in psoriasis patients was associated with psoriasis severity and subclinical CVD, and was shown to be reduced in response to the effective treatment of psoriasis.

Psoriatic inflammation of the joints results in psoriatic arthritis (PsA). The skin manifestations generally precede PsA, which shares the inflammatory chronicity of psoriasis and requires systemic therapies due to a potential destructive progression. Psoriatic arthritis develops in up to 40% of psoriasis patients [ 32 , 33 , 34 , 35 , 36 , 37 , 38 ]; around 15% of psoriasis patients are thought to have undiagnosed PsA [ 39 ]. It presents clinically with dactylitis and enthesitis in oligoarticular or polyarticular patterns. The polyarticular variant is frequently associated with nail involvement [ 40 ]. Nails are specialized dermal appendages that can also be affected by psoriatic inflammation. Nail psoriasis is reported to affect more than half of psoriasis patients, and can present as the only psoriasis manifestation in 5–10% of patients [ 41 ]. The clinical presentation of nail psoriasis depends on the structure affected by the inflammatory process. Nail matrix involvement presents as pitting, leukonychia, and onychodystrophy, whereas inflammation of the nail bed presents as oil-drop discoloration, splinter hemorrhages, and onycholysis ( Figure 3 ) [ 42 ]. Psoriatic nail involvement is associated with joint involvement, and up to 80% of patients with PsA have nail manifestations [ 43 , 44 ].

Onycholysis and oil drop changes on psoriatic nail involvement.

In addition to an increased risk for cardiometabolic disease, psoriasis has been associated with a higher prevalence of gastrointestinal and chronic kidney disease. Susceptibility loci shared between psoriasis and inflammatory bowel disease support this association in particular with regard to Crohn’s disease [ 45 , 46 ]. An association with mild liver disease, which correlates with imaging studies, has been reported [ 30 , 47 ]. Psoriasis might be a risk factor for chronic kidney disease and end-stage renal disease, independent of traditional risk factors (demographic, cardiovascular, or drug-related) [ 48 ].

Taken together, the different factors contributing to psoriasis as a systemic disease can have a dramatic effect on the quality of life of patients and their burden of disease. Psoriasis impairment to psychological quality of life is comparable to cancer, myocardial infarction, and depression [ 49 ]. The high burden of disease is thought to be owed to the symptoms of the disease, which include pain, pruritus, and bleeding, in addition to the aforementioned associated diseases [ 50 ]. The impact of psoriasis on psychological and mental health is currently an important consideration due to the implications of the disease on social well-being and treatment. Patients with psoriasis have an increased prevalence of depression and anxiety and suicidal ideation. Interestingly, psoriasis treatment leads to improvement in anxiety symptoms [ 51 , 52 ].

2. Pathogenesis

The hallmark of psoriasis is sustained inflammation that leads to uncontrolled keratinocyte proliferation and dysfunctional differentiation. The histology of the psoriatic plaque shows acanthosis (epidermal hyperplasia), which overlies inflammatory infiltrates composed of dermal dendritic cells, macrophages, T cells, and neutrophils ( Figure 4 ). Neovascularization is also a prominent feature. The inflammatory pathways active in plaque psoriasis and the rest of the clinical variants overlap, but also display discrete differences that account for the different phenotype and treatment outcomes.

Histopathology of psoriasis. ( A ) Psoriasis vulgaris characteristically shows acanthosis, parakeratosis, and dermal inflammatory infiltrates. ( B ) In pustular psoriasis, acanthotic changes are accompanied by epidermal predominantly neutrophilic infiltrates, which cause pustule formation.

2.1. Main Cytokines and Cell Types in Plaque Psoriasis

Disturbances in the innate and adaptive cutaneous immune responses are responsible for the development and sustainment of psoriatic inflammation [ 53 , 54 ]. An activation of the innate immune system driven by endogenous danger signals and cytokines characteristically coexists with an autoinflammatory perpetuation in some patients, and T cell-driven autoimmune reactions in others. Thus, psoriasis shows traits of an autoimmune disease on an (auto)inflammatory background [ 55 ], with both mechanisms overlapping and even potentiating one another.

The main clinical findings in psoriasis are evident at the outermost layer of the skin, which is made up of keratinocytes. However, the development of the psoriatic plaque is not restricted to inflammation in the epidermal layer, but rather is shaped by the interaction of keratinocytes with many different cell types (innate and adaptive immune cells, vasculature) spanning the dermal layer of the skin. The pathogenesis of psoriasis can be conceptualized into an initiation phase possibly triggered by trauma (Koebner phenomenon), infection, or drugs [ 53 ] and a maintenance phase characterized by a chronic clinical progression (see Figure 5 ).

The pathogenesis of psoriasis.

It is well known that dendritic cells play a major role in the initial stages of disease. Dendritic cells are professional antigen-presenting cells. However, their activation in psoriasis is not entirely clear. One of the proposed mechanisms involves the recognition of antimicrobial peptides (AMPs), which are secreted by keratinocytes in response to injury and are characteristically overexpressed in psoriatic skin. Among the most studied psoriasis-associated AMPs are LL37, β-defensins, and S100 proteins [ 56 ]. LL37 or cathelicidin has been attributed a pathogenic role in psoriasis. It is released by damaged keratinocytes, and subsequently forms complexes with self-genetic material from other damaged cells. LL37 bound to DNA stimulates toll-like receptor (TLR) 9 in plasmacytoid dendritic cells (pDCs) [ 57 ]. The activation of pDC is key in starting the development of the psoriatic plaque, and is characterized by the production of type I IFN (IFN-α and IFN-β). Type I IFN signaling promotes myeloid dendritic cells (mDC) phenotypic maturation, and has been implicated in Th1 and Th17 differentiation and function, including IFN-γ and interleukin (IL)-17 production, respectively [ 58 , 59 , 60 ].

Whilst LL37–DNA complexes stimulate pDCs through TLR9, LL37 bound to RNA stimulates pDCs through TLR7. In addition, LL37–RNA complexes act on mDCs via TLR8 [ 56 , 57 ]. Activated mDCs migrate into draining lymph nodes and secrete tumor necrosis factor (TNF)-α, IL-23, and IL-12, with the latter two modulating the differentiation and proliferation of Th17 and Th1 cell subsets, respectively. Furthermore, slan + monocytes, which are important pro-inflammatory cells found in psoriasis skin lesions, respond to LL37–RNA activation by secreting high amounts of TNF-α, IL-12, and IL-23 [ 61 ].

The activation of the adaptive immune response via the distinct T cell subsets drives the maintenance phase of psoriatic inflammation [ 62 ]. Th17 cytokines, namely IL-17, IL-21, and IL-22 activate keratinocyte proliferation in the epidermis.

The inflammatory milieu activates keratinocyte proliferation via TNF-α, IL-17, and IFN-γ. Keratinocytes are also activated by LL37 and DNA, and greatly increase the production of type I IFNs [ 57 ]. Furthermore, they participate actively in the inflammatory cascade through cytokine (IL-1, IL-6, and TNF-α), chemokine, and AMP secretion.

A widely used psoriasis-like inflammation mouse model relies on the effect of the TLR7/8 agonist imiquimod, and is thus in support of the TLR7/8 disease initiation model. In addition, the response to imiquimod was blocked in mice deficient of IL-23 or IL-17R, which highlights the involvement of the IL-23/IL-17 axis in skin inflammation and psoriasis-like pathology [ 63 ].

The TNFα–IL-23–Th17 inflammatory pathway characterizes plaque-type psoriasis. The IL-17 cytokine family is composed of six members: IL-17A–F. They are produced by different cell types, and are important regulators of inflammatory responses [ 64 ]. So far, the clinically relevant signaling in psoriasis is mediated mostly by IL-17A and IL-17F; both act through the same receptor, but have different potencies. IL-17A exerts a stronger effect than IL-17F, and the IL-17A/IL-17F heterodimer has an intermediate effect. IL-17A binds to its trimeric receptor complex composed of two IL-17RA subunits and one IL-17RC subunit, resulting in the recruitment of the ACT1 adaptor protein. The interaction between ACT1 and the IL-17 receptor complex leads to the activation of a series of intracellular kinases including: extracellular signal-regulated kinase (ERK), p38 MAPK, TGF-beta-activated Kinase 1 (TAK1), I-kappa B kinase (IKK), and glycogen synthase kinase 3 beta (GSK-3 beta). These kinases enable NFκB, AP-1, and C/EBP transcription of pro-inflammatory cytokines, chemokines, and antimicrobial peptides. Th1 and Th2 cytokines act through Janus kinase (JAK)-STAT signaling pathways, whereas Th17 responses are mediated by ACT1 and NFκB [ 65 ]. Alternatively, γδ T cells are able to produce IL-17A independently of the IL-23 stimulus [ 66 ].

Drugs targeting TNFα, IL-23, and IL-17 and signaling pathways such as JAK/STAT are effective in the clinical management of plaque psoriasis. However, alternate inflammatory pathways may be valid for distinct psoriatic variants.

2.2. Pathophysiology in Variants

Whereas the TNFα–IL23–Th17 axis plays a central role in T cell-mediated plaque psoriasis, the innate immune system appears to play a more prominent role in the pustular variants of psoriasis [ 55 ]. Different pathomechanisms are associated with distinct psoriasis subtypes.

In guttate psoriasis, streptococcal superantigens are thought to stimulate the expansion of T cells in the skin [ 67 ]. It was shown that there is a considerable sequence homology between streptococcal M proteins and human keratin 17 proteins. Molecular mimicry may play a role in patients with the major histocompatibility HLA-Cw6 allele, since CD8(+) T cell IFN-γ responses were elicited by K17 and M6 peptides in said patients [ 68 , 69 ].

Pustular psoriasis is characterized by the increased expression of IL-1β, IL-36α, and IL-36γ transcripts, which have been found in pustular psoriasis compared to psoriasis vulgaris [ 70 ]. Nevertheless, IL-17 signaling is also involved in pustular psoriasis and patients with generalized pustular psoriasis without IL-36R mutations responded to anti-IL-17 treatments [ 71 , 72 ].

In nail psoriasis and psoriatic arthritis (PsA), an increased expression of TNF-α, NFκB, IL-6, and IL-8 in psoriasis-affected nails is consistent with the inflammatory markers found on lesional psoriatic skin [ 73 ]. The pathophysiology of PsA and psoriasis is shared as synovial tissue in psoriatic arthritis expresses pro-inflammatory cytokines: IL-1, IFN-γ, and TNFα [ 74 , 75 ]. Infiltrating cells in psoriasis arthritis, tissues, and synovial fluid revealed large clonal expansions of CD8 + T cells. Joint pathology, specifically bone destruction, is partly mediated via IL-17A signaling, which induces the receptor activator of nuclear factor kappa b ligand (RANKL), and in turn activating osteoclasts. Pro-inflammatory cytokines IL-1β and TNF-α act in synergy with the local milleu [ 76 ].

2.3. Autoimmunity in Psoriasis

Psoriasis shows clear autoimmune-related pathomechanisms. This very important area of research will allow for a deeper understanding of to which extent autoantigen-specific T cells contribute to the development, chronification, and overall course of the disease.

LL37 is one of two well-studied T cell autoantigens in psoriasis. CD4 + and CD8 + T cells specific for LL37 were found in two-thirds of patients with moderate to severe plaque psoriasis in a study. LL37-specific T cells produce IFN-γ, and CD4 + T cells produce IL-17, IL-21, and IL-22 as well. LL37-specific T cells can be found in lesional skin or in the blood, where they correlate with disease activity [ 77 ]. CD8 + T cells activated through LL37 engage in epidermotropism, autoantigen recognition, and the further secretion of Th17 cytokines. The melanocytic protein ADAMTSL5 was found to be an HLA-C*06:02-restricted autoantigen recognized by an autoreactive CD8 + T cell TCR. This finding establishes melanocytes as autoimmune target cells, but does not exclude other cellular targets [ 78 ].

Other autoantigen candidates include lipid antigens generated by phospholipase A2 (PLA2) group IVD (PLA2G4D) and hair follicle-derived keratin 17 [ 79 , 80 ]. Interestingly, keratin 17 exposure only lead to CD8+ T cell proliferation in patients with the HLA-Cw*0602 allele (see above) [ 81 ].

2.4. Genetics

Psoriasis has a genetic component that is supported by patterns of familial aggregation. First and second-degree relatives of psoriasis patients have an increased incidence of developing psoriasis, while monozygotic twins have a two to threefold increased risk compared to dizygotic twins [ 82 , 83 ]. Determining the precise effect of genetics in shaping innate and adaptive immune responses has proven problematic for psoriasis and other numerous immune-mediated diseases [ 84 , 85 ]. The genetic variants associated with psoriasis are involved in different biological processes, including immune functions such as antigen presentation, inflammation, and keratinocyte biology [ 55 ].

2.4.1. Antigen Presentation

Genome-wide linkage studies of psoriasis-affected families have so far detected at least 60 chromosomal loci linked to psoriatic susceptibility [ 86 , 87 , 88 ]; the most prominent locus is PSORS1, which has been attributed up to 50% of the heritability of the disease [ 89 ]. PSORS1 is located on chromosome 6p21 within the major histocompatibility complex (MHC), which is specifically in the class I telomeric region of HLA-B, and spans an approximately 220 kb-long segment and corresponds to HLA-Cw6 (C*06:02). HLA-Cw6 is strongly linked to early and acute onset psoriasis [ 90 , 91 ]. The HLA-C*06:02 allele is present in more than 60% of patients, and increases the risk for psoriasis nine to 23-fold [ 92 ]. Nevertheless, no link between late-onset psoriasis or pustular psoriasis and PSORS1 could be established, possibly reflecting a genetically heterogenic background associated with different clinical phenotypes [ 93 ]. PSORS2 spans the CARD14 gene, while PSORS4 is located in the epidermal differentiation complex [ 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 ].

The results of numerous genome-wide association studies (GWAS) in psoriasis are consistent with the prominent role of PSORS1 as a risk factor, but have also revealed over 50 single-nucleotide polymorphisms (SNPs) to be associated to psoriasis [ 102 , 103 , 104 ]. Variants involving the adaptive and immune system are a constant result in these studies [ 53 , 103 , 105 ].

2.4.2. Genetic Variants Implicated in Aberrant Keratinocyte Proliferation and Differentiation

The immunogenetics of IL-23 are strongly associated with psoriasis. IL-23 is a dimer composed of a specific subunit, p19, and a p40 subunit, which is shared with IL-12. IL-23 signals through a heterodimeric receptor expressed by both innate and adaptive immune cells, which include Th17, natural killer T, γδ T cells, and RORγt + innate lymphoid cells. The IL-23R signals through JAK2/TYK2 and STAT3 [ 106 ]. SNPs in the regions coding for the IL-23 cytokine (both the p40 and p19 subunit) as well as the IL-23R have been identified to convey psoriasis risk [ 107 , 108 , 109 ]. Furthermore, these variants have been found to be associated with Crohn’s disease, psoriatic arthritis, and ankylosing spondylitis [ 110 ] [ 74 , 75 ]. IL-23 drives the expansion of Th17 T cells that produce IL-17A/F, which is another set of cytokines whose role is pivotal in the pathogenesis of psoriasis. Monoclonal antibodies targeting both the common p40 and the specific p19 subunit of IL-23 have proven to have high clinical efficacy [ 109 ].

As mentioned above, STAT3 is found in downstream signaling by IL-23, and is therefore essential in T cell development and Th17 polarization. STAT3 has also been detected in psoriasis GWAS, and its variants are associated with psoriasis risk [ 107 , 111 ]. Furthermore, transcription factor Runx1 induces Th17 differentiation by interacting with RORγt. Interestingly, the interaction of Runx1 with Foxp3 results in reduced IL-17 expression [ 112 ].

CARD14 mapping was shown to correspond to PSORS2. The CARD family encompasses scaffolding proteins that activate NF-kB. It was suggested that in psoriasis patients with respective CARD14 mutations, a triggering event can result in an aberrant NF-kB over activation [ 96 ]. CARD14 is expressed in keratinocytes and in psoriatic skin; it is upregulated in the suprabasal epidermal layers and downregulated in the basal layers. In healthy skin, CARD14 is mainly localized in the basal layer. Mutations in CARD14 have been shown to be associated with psoriasis, as well as with familial pityriasis rubra pilaris (PRP) [ 113 ].

The NF-kB signaling pathway is involved in the production of both IL-17 and TNF-α, and thus participates in adaptive and innate immune responses [ 73 ]; it is upregulated in psoriatic lesions and is responsive to treatment [ 114 ]. Gene variations in NFKBIA, TNIP1 , and TRAF3PI2 affecting NF-kB regulatory proteins have been linked to psoriasis via GWAS [ 102 , 115 , 116 , 117 ]. TRAF3PI2 codes for the ACT1 adaptor protein and the specific variant TRAF3IP2 p. Asp10Asn was associated to both psoriasis and psoriatic arthritis [ 117 ].

The different clinical psoriasis variants may have additional genetic modifiers. For instance, mutations in the antagonist to the IL-36 receptor (IL-36RN), belonging to the IL-1 pro-inflammatory cytokine family, have been linked to pustular psoriasis [ 118 , 119 ]. Recessive mutations in IL36RN , coding for the IL-36 receptor antagonist, have been associated with generalized pustular psoriasis (GPP). This mutation is also found in palmar plantar pustulosis and acrodermatitis continua of Hallopeau. Furthermore, in patients with pre-existing plaque-type psoriasis, the gain of function mutation in CARD14 , p.Asp176His, was found to be a predisposing factor for developing GPP [ 120 ].

In addition to studies of genetic variants, the profiling of gene expression in psoriasis has aided in the understanding of the relevant pathophysiological pathways. Transcriptomic studies of psoriatic skin have revealed differentially expressed genes (DEGs) when compared to healthy skin, and also between lesional and nonlesional psoriatic skin [ 121 , 122 ]. Further underscoring their relevance in psoriasis pathogenesis, IL-17A genes were found to be upregulated in nonlesional psoriatic skin compared to healthy skin. This finding suggests that nonlesional psoriatic skin is also subclinically affected, and supports the concept of the widespread inflammation that is present in psoriasis [ 123 ]. In addition, data showing the upregulation of Th2 genes in nonlesional psoriatic skin may reflect the activation of T cell regulatory compensation mechanisms in an effort to override the inflammatory cascade [ 123 ]. ‘Cross-disease’ transcriptomics have aided in differentiating nonspecific DEGs present in inflammatory skin conditions (such as atopic dermatitis and squamous cell carcinoma) from DEGs specific to psoriasis. The latter are induced by IL-17A and are expressed by keratinocytes [ 124 ].

Despite solid evidence of genetic relevance in the pathogenesis of psoriasis, no single genetic variant seems to be sufficient to account on its own for the development of disease. Hence, a multifactorial setting including multiple genetic mutations and environmental factors, which have been attributed up to 30% of disease risk, ought to be considered [ 125 ].

2.5. Epigenetics

The quest for the missing heritability associated with psoriasis candidate genes has fueled the search for epigenetic modifications. Epigenetic mechanisms modify gene expression without changing the genomic sequence; some examples include: long noncoding RNA (lncRNA), microRNA (miRNA) silencing, and cytosine and guanine (CpG) methylation.

lncRNA are at least 200 nucleotides long, and are not transcribed to protein. At least 971 lncRNAs have been found to be differentially expressed in psoriatic plaques compared to normal skin [ 126 , 127 , 128 , 129 , 130 , 131 ]. Thereof, three differentially expressed lncRNAs in proximity to known psoriasis susceptibility loci at CARD14, LCE3B/LCE3C , and IL-23R , and are thought to modulate their function [ 127 ].

miRNAs are small, evolutionarily conserved, noncoding RNAs that base pair with complementary sequences within mRNA molecules, and regulate gene expression at the posttranscriptional level, usually downregulating expression. Most of the studies of miRNAs in association with psoriasis address the plaque-type variant (see Table 1 ), and so far, more than 250 miRNAs are aberrantly expressed in psoriatic skin [ 132 , 133 , 134 , 135 ]. A prominent role has been attributed to miR-31, which is upregulated in psoriatic skin and regulates NF-κB signaling as well as the leukocyte-attracting and endothelial cell-activating signals produced by keratinocytes [ 135 ]. miR-21 is an oncomiR with a role in inflammation, and has been found to be elevated in psoriatic skin. Increased miR-21 has been localized not only to the epidermis, but is also found in the dermal inflammatory infiltrates, and correlates with elevated TNF-α mRNA expression [ 136 ]. miR-221 and miR-222 are among other upregulated miRNAs in psoriatic skin [ 132 ]. The aberrant expression of miR-21, miR-221, and miR-222 correlates with a downregulation of the tissue inhibitor of metalloprotease 3 (TIMP3) [ 137 , 138 ]. TIMP3 is a member of the matrix metalloprotease family with a wide range of functions. Increased levels of said miRs are thought to result in unopposed matrix metalloprotease activity, leading to inflammation (partly via TNF-α-mediated signaling) and epidermal proliferation [ 138 ]. miR-210 was found to be highly expressed in psoriasis patients, and induced Th17 and Th1 differentiation while inhibiting Th2 differentiation through STAT6 and LYN repression [ 139 ].

MicroRNAs (miRNAs) increased in psoriasis.

Serum levels of miR-33, miR-126, and miR-143, among others, have been proposed as potential biomarkers of disease [ 140 , 141 ]. However, the studies have so far failed to consistently present elevations of a single miRNA in psoriatic patients. Thus, alterations of miRNA expression are better interpreted in the context of miRNA profiles, which have been reported to shift following psoriasis treatments [ 132 ]. Thus, miRNA expression profiles could potentially be used to predict response to treatment and personalize therapies.

DNA methylation is another epigenetic mechanism that can alter gene expression in a transient or heritable fashion, and primarily involves the covalent modification of cytosine and guanine (CpG) sequences. CpG methylation is usually repressive unless it inhibits transcriptional repressors, in which case it results in gene activation. Around 1100 differentially methylated CpG sites were detected between psoriatic and control skin. Of these sites, 12 corresponded to genes regulating epidermal differentiation, and were upregulated due to a lower methylation pattern. Said changes in DNA methylation reverted to baseline under anti-TNF-α treatment, indicating that CpG methylation in psoriasis is dynamic [ 148 , 149 ]. Further research will shed light on the functional relevance of epigenetic regulation in psoriasis.

2.6. Microbiome

The skin microbiome exerts an active role in immune regulation and pathogen defense by stimulating the production of antibacterial peptides and through biofilm formation. A differential colonizing microbiota in comparison to healthy skin has been found in several dermatologic diseases, including atopic dermatitis, psoriasis, and acne vulgaris [ 150 , 151 ]. It is hypothesized that an aberrant immune activation triggered by skin microbiota is involved in the pathogenesis of autoimmune diseases. For instance, there is growing evidence that the steady-state microbiome plays a role in autoimmune diseases such as in inflammatory bowel disease [ 152 ].

The overall microbial diversity is increased in the psoriatic plaque [ 151 ]. However, an increase in Firmicutes and Actinobacteria phyla were found in psoriatic plaques ( Table 2 ) [ 153 ]. Proteobacteria were found to be higher in healthy skin when compared to psoriatic patients [ 153 , 154 ]. Nevertheless, Proteobacteria were found to be increased in the trunk skin biopsies of psoriatic lesions [ 151 ]. A combined increase in Corynebacterium, Propionibacterium, Staphylococcus, and Streptococcus was found in psoriatic skin; however, in another study, Staphylococci were significantly lower in psoriatic skin compared to healthy controls [ 151 , 154 ].

Psoriasis microbiome. ↑ increased. > higher than.

Certain fungi such as Malassezia and Candida albicans, and viruses such as the human papilloma virus have been associated with psoriasis [ 155 ]. So far, Malassezia proved to be the most abundant fungus in psoriatic and healthy skin. Nevertheless, the colonization level of Malassezia in psoriasis patients was lower than that in healthy controls [ 156 ]. Further studies are required to explain the role of the microbiome signature and the dynamics among different commensal and pathogenic phyla [ 157 ].

Psoriasis is a chronic relapsing disease, which often necessitates a long-term therapy. The choice of therapy for psoriasis is determined by disease severity, comorbidities, and access to health care. Psoriatic patients are frequently categorized into two groups: mild or moderate to severe psoriasis, depending on the clinical severity of the lesions, the percentage of affected body surface area, and patient quality of life [ 159 ]. Clinical disease severity and response to treatment can be graded through a number of different scores. The PASI score has been extensively used in clinical trials, especially those pertaining to the development of the biologic drugs, and will be used throughout this review.

Mild to moderate psoriasis can be treated topically with a combination of glucocorticoids, vitamin D analogues, and phototherapy. Moderate to severe psoriasis often requires systemic treatment. The presence of comorbidities such as psoriasis arthritis is also highly relevant in treatment selection. In this review, we will address the systemic therapies as small-molecule (traditional and new) and biologic drugs.

A number of case reports and case series have suggested that tonsillectomy has a therapeutic effect in patients with guttate psoriasis and plaque psoriasis [ 69 , 160 , 161 ]. A systematic review concluded that the evidence is insufficient to make general therapeutic recommendations for tonsillectomy, except for selected patients with recalcitrant psoriasis, which is clearly associated to tonsillitis [ 162 ]. A recent study stated that HLA-Cw*0602 homozygosity in patients with plaque psoriasis may predict a favorable outcome to tonsillectomy [ 163 ]. To date, a single randomized, controlled clinical trial showed that tonsillectomy produced a significant improvement in patients with plaque psoriasis in a two-year follow-up timespan [ 164 ]. Furthermore, the same cohort was evaluated to assess the impact of the clinical improvement after tonsillectomy on quality of life. The study reported a 50% improvement in health-related quality of life, and a mean 59% improvement in psoriasis-induced stress. Tonsillectomy was considered worthwhile by 87% of patients who underwent the procedure [ 165 ].

3.1. Small-Molecule Therapies

In the past years, an accelerated development in psoriasis therapies has resulted in advanced targeted biological drugs. Methotrexate (MTX), cyclosporin A, and retinoids are traditional systemic treatment options for psoriasis. All of the former are oral drugs with the exception of MTX, which is also available for subcutaneous administration. They will be briefly discussed in this review (see Table 3 ). The section ends with an overview on dimethyl fumarate and apremilast, which are newer drugs that have been approved for psoriasis.

Drugs available for psoriasis therapy.

MTX is a folic acid analogue that inhibits DNA synthesis by blocking thymidine and purine biosynthesis. The initial recommended dose of 7.5–10 mg/weekly may be increased to a maximum of 25 mg/weekly [ 166 , 167 ]. A recent retrospective study reported successful treatment response (defined by PASI decrease of 50% to 75% and absolute DLQI value) was reached by 33%, 47%, and 64% of patients at three, six, and 12 months, respectively [ 168 ]. There is conflicting evidence regarding MTX effectiveness on psoriatic arthritis. A recent publication reported 22.4% of patients achieved minimal arthritic disease activity, and 27.2% reached a PASI 75 at week 12 [ 169 ]. Furthermore, HLA-Cw6 has been suggested as a potential marker for patients who may benefit from MTX treatment [ 170 ]. The most common side effects include nausea, leucopenia, and liver transaminase elevation. Despite the potential side effects and its teratotoxicity, it remains a frequently used cost-effective first-line drug, and the close monitoring of liver function and full blood count make a long-term administration feasible.

Cyclosporine is a T cell-inhibiting immunosuppressant from the group of the calcineurin inhibitors. Cyclosporine is effective as a remission inducer in psoriasis and as maintenance therapy for up to two years [ 171 ]. Hypertension, renal toxicity, and non-melanoma skin cancer are significant potential side effects. Nephrotoxicity is related to the duration of treatment and the dose. Cyclosporine is employed as an intermittent short-term therapy. The dosage is 2.5 to 5.0 mg/kg of body weight for up to 10 to 16 weeks. Tapering of the drug is recommended to prevent relapse [ 171 ].

Retinoids are natural or synthetic vitamin A-related molecules. Acitretin is the retinoid used in the treatment of psoriasis. It affects transcriptional processes by acting through nuclear receptors and normalizes keratinocyte proliferation and differentiation [ 172 , 173 ]. A multicenter, randomized study reported 22.2% and 44.4% of patients reaching PASI 75 and PASI 50 at 24 weeks [ 174 ]. Acitretin is initially administered at 0.3–0.5 mg/kg of body weight per day. The maximum dosage is 1 mg/kg body weight/daily. Cheilitis is the most common side effect appearing dose dependently in all patients. Other adverse effects include conjunctivitis, effluvium, hepatitis, and teratogenicity.

Fumaric acid esters (FAEs) are small molecules with immunomodulatory and anti-inflammatory properties [ 175 , 176 ]. The exact mechanism of action has not been cleared, but is thought to involve an interaction with glutathione, which among other mechanisms, inhibits the transcriptional activity of NF-κB [ 177 , 178 ]. FAEs were initially available as a mix of dimethyl fumarate and monoethyl fumarate (DMF/MEF), the former being the main active compound in the formulation. DMF has been reported to decrease the migratory capacity of slan+ monocytes, and also inhibited the induction of Th1/Th17 responses [ 178 ]. DMF/MEF was approved in 1994 in Germany for the treatment of severe plaque psoriasis, and in 2008, the indication was expanded for moderate psoriasis [ 179 ]. This licensing was exclusive to Germany, where it remains a first-line drug; nevertheless, DMF/MEF was used as off-label treatment in other European countries [ 180 , 181 , 182 , 183 ]. A new FAE formulation containing exclusively the main active metabolite DMF became available in 2017, and was approved for psoriasis treatment in the European Union, Iceland, and Norway [ 184 ]. Although there are no studies comparing DMF/MEF directly to biologics, several studies document its efficacy [ 185 , 186 , 187 , 188 , 189 ]. A marked improvement is also seen in patients with psoriatic arthritis and nail psoriasis. The most common side effects are gastrointestinal symptoms and flushing, which are generally mild in severity, resolve over time, and are dose related [ 184 ]. In addition, FAEs may decrease lymphocyte and leukocyte counts. Therefore, it is recommended to perform a complete blood count before treatment initiation and monthly for DMF/MEF or every three months for DMF [ 184 ].

Apremilast, a phosphodiesterase-4 inhibitor, inhibits the hydrolyzation of the second messenger cAMP. This leads to the reduced expression of pro-inflammatory cytokines TNF-α, IFN0γ, and IL-12, and increased levels of IL-10. Apremilast was shown to have broad anti-inflammatory effects on keratinocytes, fibroblasts, and endothelial cells [ 190 ]. We studied apremilast in the context of slan + cells, which is a frequent dermal inflammatory dendritic cell type derived from blood circulating slan + nonclassical monocytes. Here, apremilast strongly reduced TNF-α and IL-12 production, but increased IL-23 secretion and IL-17 production in T cells stimulated by apremilast-treated slan + monocytes [ 191 ]. These dual effects on slan + antigen-presenting cells may constrain therapeutic responses. No routine monitoring of hematologic parameters is required for apremilast, which is a major advantage compared to the other small molecule drugs. Apremilast showed a 33.1% PASI 75 response at week 16. It is also effective for palmoplantar, scalp psoriasis, and nail psoriasis in addition to psoriatic arthritis [ 192 , 193 , 194 ]. The most common adverse events affected the gastrointestinal tract (nausea and diarrhea) and the upper respiratory tract (infections and nasopharyngitis). These effects were mild in nature and self-resolving over time.

The traditional systemic drugs are immunomodulators, which except for apremilast require close clinical monitoring due to the common side effects involving mainly the kidney and the liver. Methotrexate and cyclosporine are the only systemic therapies for psoriasis included in the World Health Organization (WHO) Model List of Essential Medicines, albeit for the indications of joint disease for the former and immunosuppression for the latter. The potential side effects of FAE and apremilast are usually not life-threatening, but might be sufficient to warrant discontinuation.

3.2. Biologics

In the context of psoriasis treatment, current use of the term biologics refers to complex engineered molecules including monoclonal antibodies and receptor fusion proteins. Biologics are different from the above-described systemic therapies in that they target specific inflammatory pathways and are administered subcutaneously (s.c.) (or intravenously i.e., infliximab) on different weekly schedules. Biologics presently target two pathways crucial in the development and chronicity of the psoriatic plaque: the IL-23/Th17 axis and TNF-α-signaling (see Table 3 ).

3.2.1. TNF-α

TNF-α inhibitors have been available for over a decade. They are considered the first-generation biologics, and are effective for plaque psoriasis and psoriatic arthritis. TNF-α inhibitors are still the standard used to evaluate drug efficacy in psoriasis clinical research. There are currently four drugs in this category: etanercept, infliximab, adalimumab, and certolizumab.

Etanercept is unique in the biologics category in that it is not a monoclonal antibody, but rather a recombinant human fusion protein. The receptor portion for the TNF-α ligand is fused to the Fc portion of an IgG1 antibody. It was the first TNF-α inhibitor approved by the United States Food and Drug Administration (FDA) for psoriasis. Infliximab is a chimeric monoclonal IgG1 antibody, and adalimumab is a fully human monoclonal IgG1 antibody. They neutralize TNF-α activity by binding to its soluble and membrane-bound form. These drugs are particularly employed to treat psoriatic arthritis, and show a similar efficacy. In the treatment of psoriasis, they show different PASI 75 response rates: 52% for etanercept, 59% for adalimumab, and 80% for infliximab. Infliximab shows superiority in terms of efficacy when compared to the other TNF-α inhibitors, and when compared with ustekinumab, it showed a similar performance [ 195 ]. The chimeric nature of infliximab might contribute to a higher immunogenic potential of the drug, which in turn might influence drug survival. Certolizumab pegol is a pegylated Fab’ fragment of a humanized monoclonal antibody against TNF-α. PEGylation is the covalent conjugation of proteins with polyethylene glycol (PEG), and is attributed a number of biopharmaceutical improvements, including increased half-life and reduced immunogenicity [ 196 ]. The initial indication for treating Crohn’s disease was extended to psoriatic arthritis and recently to plaque psoriasis. Certolizumab has shown an 83% PASI 75 response. Unlike other anti-TNF-α agents, it has no Fc domain, and is thus not actively transported across the placenta. Thus, certolizumab pegol is approved for use during pregnancy and breastfeeding.

3.2.2. IL23/Th17 axis

As previously mentioned, IL-23 drives the expansion of Th17 cells whose inflammatory effects are in turn mediated by IL-17A, IL-17F, and IL-22.

IL-23 is a dimer composed of p40 and p19. The first biologic to be approved for psoriasis vulgaris after the TNF-α inhibitors was ustekinumab, which is a monoclonal antibody directed against the p40 subunit. P40 is not exclusive to IL-23, but rather is shared with IL-12. IL-12 is a dimer consisting of p40 and p35, and is involved in the differentiation of naïve T cells into Th1 cells. By targeting p40, ustekinumab blocks two different T-cell activating mechanisms, namely Th1 and Th17 selection. Ustekinumab is also effective for the treatment of PsA and Chron’s disease. It is available in two dosages, 45 mg and 90 mg, depending on a threshold body weight of 100 kg. Ustekinumab has extensive safety data, few side effects, good clinical efficacy, and long treatment drug survival was reported. At 90 mg, ustekinumab showed a PASI 75 response in 72.4% and in 61.2% at 45 mg [ 197 ]. Studies using real-life data compared ustekinumab with the anti-TNF-α drugs, and ustekinumab was found to have a significant longer drug survival [ 198 , 199 , 200 ]. Frequent adverse events include nasopharyngitis, upper respiratory tract infections, fatigue, and headache. Among the serious adverse events listed in the label of ustekinumab are infections. Tuberculosis (TB) has only been reported in two psoriasis patients receiving ustekinumab [ 201 , 202 ]. The clinical efficacy of ustekinumab and the further clarification of its mechanism of action highlighted the crucial role of IL-23 in shaping the Th17 response. On the other hand, Th1 signaling is important for the response against bacterial and viral pathogens, and a study showed IL-12 signaling to have a protective effect in a model of imiquimod psoriasis-like inflammation [ 203 ]. This rationale fueled the development of drugs targeting p19, which is the IL-23-exclusive subunit. This more specific molecular targeting approach has also achieved successful clinical outcomes. Three fully human monoclonal antibodies with p19 specificity are available: guselkumab, tildrakizumab, and risankizumab. Guselkumab is licensed for psoriasis, and showed clinical superiority when compared to adalimumab, with 85.1% of patients reaching a PASI 75, and 73.3% receiving a PASI 90 response at week 16 [ 204 , 205 ]. Patients receiving tildrakizumab showed a 74% PASI 75, and 52% PASI 90 at week 16. Tildrakizumab was compared to etanercept, and was more likely to reach PASI 75 at weeks 16 and 28 [ 206 , 207 ]. Risankizumab showed the following PASI responses at week 12: 88% PASI 75, 81% PASI 90, and 48% PASI 100. Patients were followed for 48 weeks after the last injection at week 16, and one-fourth of them showed a maintained PASI 100 [ 208 ]. Whether IL-23 inhibition has the potential to modify the course of the disease after subsequent drug retrieval is currently under study.

So far, three human monoclonal antibodies targeting IL-17 are available. Secukinumab and ixekizumab block IL-17A; whereas brodalumab is directed against the IL-17 receptor A. IL-17-targeted biologics are fast acting, showing significant differences from placebo within the first week of treatment. Secukinumab was the first IL-17A inhibitor approved for psoriasis in 2015. A year later, the approval extended to include PsA and ankylosing spondylitis. At week 12, 81.6% of patients on secukinumab reached a PASI 75 response, and 28.6% reached a PASI 100 response [ 209 ]. At week 52, over 80% maintained PASI 75. Secukinumab showed a rapid onset of action, reflecting a significant likelihood of achieving PASI 75 as early as the first week of treatment when compared to ustekinumab, and surpassed the latter in clinical superiority at week 16 and 52 [ 210 , 211 ].

Ixekizumab also showed a significantly rapid onset of action in the first week when compared to placebo: a 50% PASI 75 response at week four, and 50% PASI 90 by week eight. At week 12, response rates were 89.1% for PASI 75 and 35.3% for PASI 100 [ 212 ]. Secukinumab and ixekizumab have proven effective for scalp and nail psoriasis, which are two clinical variants that are resistant to conventional topical therapies.

Brodalumab is a human monoclonal antibody that targets the IL-17 receptor type A, thus inhibiting the biological activity of IL-17A, IL-17F, interleukin-17A/F, and interleukin-17E (also called interleukin-25). Brodalumab showed an 83.3% PASI 75, 70.3% PASI 90, and 41.9% PASI 100 response rate at week 12, and a satisfactory safety profile [ 213 , 214 ]. After the discontinuation of treatment with secukinumab, 21% of patients maintained their response after one year and 10% after two years [ 215 ]. This finding suggests that targeting IL-17 signaling exerts some disease-modifying effect that might reestablish the homeostasis of the inflammatory pathways in a subset of psoriasis patients. Frequent adverse effects under IL-17 blockade include nasopharyngitis, headache, upper respiratory tract infection, and arthralgia. Furthermore, IL-17 signaling is critical for the acute defense against extracellular bacterial and fungal infections. Candida infections are more frequent in patients receiving anti-IL17 biologics secukinumab and ixekizumab compared to etanercept [ 209 ]. Nonetheless, candida infections were not severe, and did not warrant treatment interruption. The risk of tuberculosis reactivation is considered small under biologic therapies other than anti-TNF-α [ 216 ]. Anti-IL-17 biologics should not be used in psoriasis patients also suffering from Chron’s disease.

3.2.3. Biosimilars in Psoriasis

The introduction of biosimilars for different diseases is revolutionizing the pharmaceutical arsenal at hand. As patents for many biologics face expiration, biosimilar versions of these drugs are being developed, or are already entering the market. A biosimilar is a biological product that must fulfill two requirements: it must be highly similar to an approved biologic product and have no clinically meaningful differences in safety, purity, or potency when compared with the reference product. Guidelines for the development and approval of biosimilars have been issued by the European Medicines Agency, the FDA, and the World Health Organization. There are currently eight adalimumab biosimilars, four infliximab biosimilars, and two etanercept biosimilars approved in Europe. By lowering the costs of systemic treatment for psoriasis patients, biosimilars may also increase access to biologics.

3.2.4. Drugs in the Research Pipeline

Tofacitinib is an oral Janus kinase (JAK) inhibitor currently approved for the treatment of rheumatoid arthritis (RA) and PsA. Tofacitinib showed a 59% PASI 75 and 39% PASI 90 response rate at week 16, and was also effective for nail psoriasis; however, its development for psoriasis was halted for reasons unrelated to safety. Upadacitinib is another JAK inhibitor currently undergoing phase III clinical trials for the treatment of psoriatic arthritis. Piclidenoson, an adenosine A3 receptor inhibitor, serlopitant, a neurokinin-1 receptor antagonist, and RORγt inhibitors are each being tested as oral treatments for psoriasis [ 217 ]. Two different biologics targeting IL-17 and one targeting IL-23 are being currently tested. In addition, there are currently 13 registered phase III clinical trials testing biosimilars for adalimumab (eight), infliximab (three), and etanercept (two).

Psoriasis is a complex multifactorial disease for which various novel therapies have arisen in the past years. In spite of the refinement of the targeted therapies, psoriasis remains a treatable but so far not curable disease. The targeted therapies show high clinical efficacy for the inhibition of IL-23 and IL-17. Some degree of a persistent antipsoriatic effect by these therapies could be demonstrated after drug discontinuation, and argue for disease modification concept [ 208 , 215 ]. This important finding will be followed up in ongoing and future studies. However, in other cases, an initial clinical response is only short lived, requiring treatment with a different biologic. Clearly, more research is required to answer the question of why the drug survival of some biologics is limited. The therapeutic arsenal for psoriasis is likely to increase in the near future, with studies on orally applied new small molecules such as inhibitors targeting RORγt. In spite of the safety and efficacy of targeted therapies, due to economic factors, dosage regimes, and adverse effect profiles, broader-acting drugs remain the mainstay of psoriasis systemic therapy in many clinical scenarios around the world. The role of genetics remains to be elucidated not only in the context of predisposition to disease, but also in the profiling of distinct psoriatic types based on cytokine signatures, and in identifying therapy response markers. Clearly, psoriasis is currently the best understood and the best treatable Th17-biased chronic inflammatory disease. After achieving excellent clinical responses for the majority of patients with available therapeutic approaches, the stratification of psoriasis patients to the optimal drug and ensuring the sustainability of our treatments are the major tasks to be resolved.

Acknowledgments

We kindly thank Lukas Freund for his comments on the manuscript, Galina Grabe for providing the histology images, Anja Heid and Christine Dorschel for their technical support in gathering the clinical pictures.

This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) to KS – SFB TRR 156, SCHA 1693/1-1 and project number 259332240/RTG 2099.

Conflicts of Interest

The authors declare no conflict of interest.

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Recent Advances in Psoriasis Research; the Clue to Mysterious Relation to Gut Microbiome

Affiliations.

• 1 Department of Dermatology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.
• 2 Department of Biochemistry, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.
• PMID: 32276410
• PMCID: PMC7177330
• DOI: 10.3390/ijms21072582

Psoriasis is a chronic inflammatory cutaneous disease, characterized by activated plasmacytoid dendritic cells, myeloid dendritic cells, Th17 cells, and hyperproliferating keratinocytes. Recent studies revealed skin-resident cells have pivotal roles in developing psoriatic skin lesions. The balance in effector T cells and regulatory T cells is disturbed, leading Foxp3-positive regulatory T cells to produce proinflammatory IL-17. Not only acquired but also innate immunity is important in psoriasis pathogenesis, especially in triggering the disease. Group 3 innate lymphoid cell are considered one of IL-17-producing cells in psoriasis. Short chain fatty acids produced by gut microbiota stabilize expression of Foxp3 in regulatory T cells, thereby stabilizing their function. The composition of gut microbiota influences the systemic inflammatory status, and associations been shown with diabetes mellitus, cardiovascular diseases, psychomotor diseases, and other systemic inflammatory disorders. Psoriasis has been shown to frequently comorbid with diabetes mellitus, cardiovascular diseases, psychomotor disease and obesity, and recent report suggested the similar abnormality in gut microbiota as the above comorbid diseases. However, the precise mechanism and relation between psoriasis pathogenesis and gut microbiota needs further investigation. This review introduces the recent advances in psoriasis research and tries to provide clues to solve the mysterious relation of psoriasis and gut microbiota.

Keywords: Foxp3; gut microbiome; innate lymphoid cells; psoriasis; regulatory T cells; systemic inflammation; tissue resident cells.

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Conflict of interest statement

The author declares no conflict of interest.

Pathogenesis of psoriasis. Modified from…

Pathogenesis of psoriasis. Modified from Lowes M.A. et al. Trends in Immunol 2016…

Skewed balance of tissue resident…

Skewed balance of tissue resident immune cells induces psoriasis in never-lesional skin of…

Three groups of innate lymphoid…

Three groups of innate lymphoid cells parallel three types of T helper cells.…

Expression of FOXP3 in pTreg…

Expression of FOXP3 in pTreg is unstable. Modified from Kanamori M et al.…

Foxp3-positive Tregs, but with unstable…

Foxp3-positive Tregs, but with unstable expression, would easily lose FOXP3 expression and become…

Gut microbiota regulates the balance…

Gut microbiota regulates the balance of Th17 vs. Tregs. Modified from Omenetti S…

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The Future of Climate Research at the USGS – Our Climate Science Plan is Released

The new USGS Climate Science Plan provides guidelines for conducting the bureau’s climate science, sets priorities, goals, and strategies, and identifies outcomes as well as opportunity gaps 

On September 6, the USGS released the  U.S. Geological Survey Climate Science Plan—Future Research Directions , the culmination of a two-year effort by the Climate Science Plan Writing Team. The team was charged with identifying the major climate science topics of future concern and developing an integrated approach to conducting climate science in support of the USGS, Department of the Interior (DOI), and administration priorities. The overarching purpose of the plan was to define the scope and delivery of critical climate science, identify future research directions, and outline opportunities to increase our climate science capacity and expand our research portfolio.  

Climate is one of the primary drivers of environmental change and a priority in defining science conducted across all USGS mission areas. USGS climate science provides the nation with forward-looking, evidence-based information and approaches to assist in planning for and adapting to a changing world. For the first time, the USGS Climate Science Plan provides guidelines for conducting the bureau’s climate science, emphasizing the transdisciplinary nature of the work. The plan embraces co-produced science and Indigenous Knowledge, understanding that climate change disproportionately affects less resilient communities. And no science plan would be complete without focusing on clear, consistent, and equitable communication of our scientific activities. The guidelines acknowledge the USGS’s unique climate science niche within DOI and the federal government, the role our science plays in potentially informing policy, as well as the relevance of our research for the nation, our stakeholders, and our international partners.  

The plan highlights three future climate science research directions: 1) characterizing climate change and associated impacts, 2) assessing climate change risks and developing approaches to mitigate climate change, and 3) providing climate science tools and support.  

Characterizing climate change and its impacts includes goals related to long-term, broad-scale monitoring, providing leadership on greenhouse gas emissions on DOI lands, collaborating with federal programs and other agencies to study climate impacts on ecosystems, and improving data synthesis both within the USGS and between the USGS and agency partners. Key goals related to assessing and reducing climate change risk include linking climate change impacts to risk assessments; reducing uncertainties in models and designing early warning systems; and creating decision support tools to inform and expand mitigation and adaptation measures, particularly through collaboration with land management agencies, use of nature-based solutions, or integration with federal greenhouse gas monitoring efforts. To provide climate adaptation services, the USGS’s goals are to facilitate co-production of knowledge, enhance data capabilities, build capacity through development of training curricula, and coordinate with other agencies.  

Twelve specific goals are identified to achieve these future research directions and are supported by specific strategies and expected impacts and outcomes of research investments.  

• Conduct long-term, broad-scale, and multidisciplinary measurements and monitoring and research activities to define, quantify, and predict the impacts of climate change on natural and human systems .  
• Provide leadership to standardize measuring, monitoring, reporting, and verifying greenhouse gas emissions, lateral carbon fluxes, and carbon sinks across lands managed by the DOI. 
• Provide science capacity, training, tools, and infrastructure to Tribal partners; support Tribal-led science initiatives. 
• Conduct climate change research in partnership with the broader climate science community. 
• Develop improved data synthesis methods through collaborative and open science across mission areas and between the USGS and bureau partners.  
• Translate climate change impacts into risk assessments in support of risk management strategies. 
• Develop new and improved risk assessments, models, and approaches for mitigating climate change, adapting to its impacts, and reducing uncertainties; design early warning systems for risk mitigation. 
• Investigate climate change mitigation strategies and create decision-science support tools to inform climate change mitigation and adaptation. 
• Provide a framework that facilitates knowledge co-production needed to inform policy decisions. 
• Provide access to USGS data and information through novel integration and visualization approaches. 
• Build capacity within the USGS and DOI through development of scientific training curricula. 
• Coordinate science and capacity building efforts broadly across the federal government. 

To ensure successful implementation of the USGS Climate Science Plan, the authors outline numerous opportunities, including strategic planning for workforce development, the recruitment of the next generation of climate scientists, social scientists, and support staff, and investments in long-term scientific innovation across USGS mission areas. The plan also details the existing USGS climate science capabilities to demonstrate the breadth of our work, while also identifying capacity gaps.  

By defining the USGS’s long-term climate science priorities, we can ensure that critical science themes and activities will continue and expand along with newly available data, innovative technologies, and evolving scientific and public information needs. This will position the USGS to continue to serve as one of the nation’s leading climate science agencies.  

Special thanks to the members of the writing team for their contributions : 

Tamara Wilson – Western Geographic Science Center  

Ryan Boyles – Southeast Climate Adaptation Science Center 

Nicole DeCrappeo – Northwest Climate Adaptation Science Center  

Judith Drexler – California Water Science Center  

Kevin Kroeger – Wood Hole Coastal and Marine Science Center 

Rachel Loehman – Alaska Science Center 

John Pearce – Alaska Science Center 

Mark Waldrop – Geology, Minerals, Energy, and Geophysics Science Center 

Peter Warwick – Geology, Energy, and Minerals Science Center 

Anne Wein – Western Geographic Science Center 

Sarah Zeigler – St. Petersburg Coastal and Marine Science Center 

Doug Beard – National Climate Adaptation Science Center 

Tamara Wilson   Acting   Assistant Regional Administrator, Southwest Climate Adaptation Science Center 

Research Geographer, Western Geographic Science Center 

Doug Beard   Director, National Climate Adaptation Science Center 

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New Zealand scientists discover new 'spookfish' living deep in the Pacific

It may be early to get the Halloween decorations out for most, but in the deep waters of the Pacific Ocean, spooky season is well underway.

Scientists said Tuesday they had discovered a new species of ghost shark that lives exclusively in the waters off Australia and New Zealand .

The Australasian Narrow-nosed Spookfish was found during research surveys in the Chatham Rise, an area of ocean floor east of New Zealand, according to the National Institute of Water and Atmospheric Research, based in Auckland.

Ghost sharks, also known as chimaeras, are a group of cartilaginous fish closely related to sharks and rays. The newly discovered species has several distinctive features, including a long and narrow snout, broad pectoral fins, scale-free skin and beak-like teeth.

They are largely confined to the ocean floor up to 2,600 meters (8,530 feet) deep, feeding on crustaceans such as shrimp and mollusks.

Brit Finucci, a fisheries scientist at the National Institute of Water and Atmospheric Research, gave it the scientific name Harriotta avia in memory of her grandmother.

Previously, it was considered to be part of a single globally distributed species. But research later showed that it is genetically and morphologically different from its cousins.  

"Ghost sharks always surprise me!" Finucci told NBC News on Tuesday. "It just goes to show how little we know about our oceans, particularly the deep sea."

Ghost sharks are "poorly studied" because of their remote living environment and cryptic nature, she said. This long-nosed spookfish was better researched among its kind as it is often observed on research surveys and is caught incidentally in commercial fisheries, Finucci said.

However, we still don't know their lifespan, population size or role in the ecosystem, Finucci said. "There’s still a lot to learn about ghost sharks!”

It had been suspected that the species may be different from those in other regions, but it took time to collect enough information to confirm that, Finucci said.

"We are still describing new species on a regular basis, and sometimes these discoveries have been right under our noses the whole time," she said.

Peter Guo is a fellow on NBC’s Asia Desk, based in Hong Kong.

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Kennesaw State research aims to reduce motor vehicle accidents

KENNESAW, Ga. | Sep 24, 2024

Billy Kihei, an assistant professor of computer engineering in the Southern Polytechnic College of Engineering and Engineering Technology , is leading a National Science Foundation (NSF)-sponsored research initiative that seeks to improve vehicle safety through cutting-edge sensing and communication technologies. The project focuses on Cellular Vehicle-to-Everything (C-V2X) technology, which allows vehicles to communicate directly with each other, potentially reducing up to 80% of crashes involving non-impaired drivers.

As the United States prepares to roll out the largest wireless communications technology for automotive safety, many vehicles on the road still lack this advanced technology. To address this challenge, Kihei’s team is exploring how C-V2X can be utilized to detect vehicles not equipped with the technology, using an approach known as integrated sensing and communications (ISAC).

“The concept is to use the signal from C-V2X to passively sense the environment around the vehicle,” Kihei said. “This enables the vehicle to detect potential collisions even if it is the only one transmitting.”

The research unfolds in several key stages. Initially, the focus is on theoretical analysis and the development of models to understand how C-V2X signals can be utilized for passive sensing. In this stage, they work on developing and improving simulations that can use these signals to detect obstacles and other vehicles.

Following the theoretical groundwork, the project advances to practical implementation. This phase involves setting up experiments and simulations with real-world data. The research team, including Ph.D. students and undergraduate researchers from the engineering college, builds and tests prototypes of the sensing system. The research findings will guide further refinements and expand the system’s potential applications to next-generation cellular networks and next-generation Wi-Fi.

“We are initially focused on preventing rear-end collisions. Our iterative approach ensures that the technology is refined and optimized to meet diverse needs and perform effectively in various other driving situations.” Kihei said.

The project is closely aligned with KSU’s new Ph.D. in Interdisciplinary Engineering , which focuses on integrating multiple disciplines to tackle complex problems. This research not only demonstrates the benefits of interdisciplinary collaboration but also provides students with valuable hands-on experience in groundbreaking technology.

Kihei’s work seeks to overcome significant integration challenges and advance the field of joint wireless communication and sensing technologies.

“This research addresses current challenges and sets the stage for the future of automotive safety and technology,” Kihei said. “By integrating new systems with existing infrastructure, we are paving the way for advancements that will enhance road safety and technology efficiency in the years ahead.”

Travis Stanca, a KSU graduate involved in preliminary studies of this research, expressed his excitement being a part of the research.

“Being part of this project has been an amazing experience,” Stanca said.  “This work will significantly enhance vehicle safety by providing crucial information for obstacle detection and future vehicle autonomy.”

– Story by Raynard Churchwell

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