Palmoplantar pustular psoriasis (PPPP) is characterized by activation of the IL-17A pathway (original) (raw)
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IL-17 and its role in psoriasis
Journal of Pakistan Association of Dermatology, 2017
IL-17 induces release of many cytokines (e.g. IL-6, G-CSF, GM-CSF, IL-1B, TGF-B, TNF∞), chemokines (e.g. IL-8, GRO-∞ and MCP1) and prostaglandins such as PGE2 from fibroblasts, endothelial cells, keratinocytes and macrophages. IL-17 along with IL-22 induces antimicrobial peptide production by keratinocytes. The release of cytokines results in keratinocyte and vascular response along with enhanced cell recruitment. Keratinocytes in response produce chemokines and cytokines, which specifically cause neutrophil recruitment. Il-17 also downregulates filaggrin, leading to disruption of skin barrier. IL-17A, the best-studied member of this family, is composed of 155 amino acids with molecular weight of 15KDa. It forms heterodimers or homodimers with IL-17F, binding with IL-17RA and IL17RC subunits leading to gene activation.
Asian Journal of Pharmaceutical and Clinical research, 2021
Objective: This study aimed at the evaluation of pruritus and its intensity and aggravating factors in psoriatic patients with the assessment of its relation to interleukin-17 (IL-17) expression in psoriatic lesions. Methods: The study included 50 patients with psoriasis vulgaris. A questionnaire was used for the evaluation of pruritus and its effect on the quality of life. Severity of pruritus was assessed by the visual analog scale (VAS) while clinical severity of psoriasis was assessed using psoriasis area severity index (PASI) score. Tissue immunohistochemical expression of IL-17 was assessed in psoriatic lesions and in 20 normal skin biopsies included as control. Results: Pruritus was encountered in 92% of psoriatic patients studied, 45.5% of them considered emotional stress as the main pruritus aggravating factor. Pruritus had influenced the daily activity and sleep in 91.3% of the studied patients. Mean VAS in studied cases was 5.70 ± 2.76. VAS grades were significantly associated with PASI scores and IL-17 tissue expression on univariate analysis. On multilogistic regression analysis, both IL-17 and PASI scores emerged as independent influencers of pruritus. Conclusion: Pruritus is a common symptom that affects the quality of life in psoriatic patients. IL-17 is an independent aggravating factor of pruritus in those patients. To the best of our knowledge, this is the first study evaluating the tissue expression of IL-17 in relation to pruritus. Pruritus treatment should be one of our goals while managing the psoriatic patients and anti-IL-17 may play a pivotal role in this field.
IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis
Journal of Allergy and Clinical Immunology, 2012
Background: In subjects with psoriasis, inflammation and epidermal hyperplasia are thought to be controlled by T cellderived cytokines. Evidence suggests that the T H 17 cell cytokine IL-17A (IL-17) might play a role in disease pathogenesis. Objective: We sought to understand the effect that neutralization of IL-17 has on the clinical features of psoriasis and to understand the role that IL-17 has in inflammatory pathways underlying psoriasis in human subjects. Methods: We examined skin lesions obtained from 40 subjects participating in a phase I, randomized, double-blind, placebo-controlled trial of the anti-IL-17 mAb ixekizumab (previously LY2439821) in which subjects received 5, 15, 50, or 150 mg of subcutaneous ixekizumab or placebo at weeks 0, 2, and 4. Results: There were significant dose-dependent reductions from baseline in keratinocyte proliferation, hyperplasia, epidermal thickness, infiltration into the dermis and epidermis by T cells and dendritic cells, and keratinocyte expression of innate defense peptides at 2 weeks. By week 6, the skin appeared normal. Quantitative RT-PCR and microarrays revealed an ablation of the disease-defining mRNA expression profile by 2 weeks after the first dose of study drug. The effect of IL-17 blockade on expression of genes synergistically regulated by IL-17 and TNF-a was of higher magnitude at 2 weeks than in prior studies with TNF-a antagonism. Conclusion: Our data suggest that IL-17 is a key ''driver'' cytokine that activates pathogenic inflammation in subjects with psoriasis. Neutralizing IL-17 with ixekizumab might be a successful therapeutic strategy in psoriasis. (J Allergy Clin Immunol 2012;130:145-54.)
Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin
British Journal of Dermatology, 2009
Background Th17 cells are a lineage of proinflammatory T helper cells producing interleukin (IL)-17. The importance of Th17 cells in inflammation and autoimmunity has now been recognized. The IL-17 cytokine family consists of six isoforms (IL-17A-IL-17F) whereas five members of the IL-17 receptor (IL-17R) family have been identified (IL-17RA-IL-17RE). Objectives To characterize the expression of the IL-17 isoforms and receptors in lesional and nonlesional psoriatic skin. Methods Keratome and punch biopsies taken from patients with psoriasis were examined by enzyme-linked immunosorbent assay and quantitative reverse transcription-polymerase chain reaction in order to measure the IL-17 isoforms and receptors. Results We demonstrated significantly increased mRNA expression of IL-17A, IL-17C and IL-17F in psoriatic skin. In contrast, the mRNA expression of IL-17B and IL-17D was significantly decreased in lesional compared with nonlesional skin, while IL-17E mRNA was undetectable. The increased mRNA expression of IL-17A, IL-17C and IL-17F was paralleled by an increased protein accumulation of these cytokines in psoriatic skin. Analysis of the IL-17R mRNA expression revealed significantly impaired mRNA expression of IL-17RB, IL-17RC, IL-17RD and IL-17RE in lesional psoriatic skin, whereas the mRNA expression of IL-17RA was similar in lesional and nonlesional psoriatic skin. Conclusions This study characterizes the mRNA profile of the IL-17 isoforms and receptors in psoriatic skin lesions. Furthermore, we demonstrate for the first time augmented protein levels of IL-17A, IL-17C and IL-17F in psoriatic skin lesions, indicating a possible role for IL-17C in addition to IL-17A and IL-17F in the pathogenesis of psoriasis.
Krüppel-like factor 4 (KLF4) is a transcription factor that regulate a diverse array of cellular processes, including development, differentiation, proliferation and apoptosis. The role of its function regarding keratinocytes has been widely studied, yet its exact role or function has not been elucidated. The objective of the study was to investigate the epidermal expression level of KLF4 in normal healthy donor skin and psoriatic lesional and non-lesional skin, and determine its roles of KLF4 in psoriasis. We compared the epidermal expression level of KLF4 in normal healthy donor skin and psoriatic lesional and non-lesional skin immunohistochemically and measured the epidermal level of KLF4 with RT-PCR. We also performed epidermal proliferation after knocking down of KLF4, using siRNA to evaluate the growth of keratinocyte in HaCaT cells. The entire epidermis, especially the suprabasal layer of the psoriatic epidermis showed increased KLF4 expression compared to the normal, non-lesional skin. After treatment, the expression level in the suprabasal layer of the psoriasis skin was decreased. The epidermal level of KLF4, as measured by RT-PCR, was increased after the treatment of the psoriasis skin and the proliferation of HaCaT cells was changed by knockingdown the KLF4 mRNA. In conclusion, these data demonstrates that KLF4 can be an important regulator in epidermal proliferation and can be associated with epidermal proliferation disorders, including psoriasis. Background: The contribution of to the pathogenesis of psoriasis is substantiated by the clinical efficacy of antibodies against the common IL-12/IL-23 subunit p40, like Ustekinumab, suppressing IL-17 and Th1 cytokine production. To further address the significance of IL-17 producing T cell subsets in psoriasis, CD18hypo PL/J mice, developing a psoriasiform dermatitis at 12-14 weeks of age as a consequence of reduced expression of CD18/β2 integrin to 2-16 % of wildtype levels, were systematically analyzed for the presence of gammadelta and CD4+ T cell subsets in blood, lymphnodes and skin and the effect of blocking different targets within the IL-23/IL-17 axis. Results: Severity of CD18hypo PL/J psoriasiform dermatitis generally correlated with a loss of skin-resident Vγ5+ T cells and concurrent skin infiltration with inflammatory γδTCR-low expressing Vγ4+ and Vγ6+ T cells preceded by an increase of IL-23R+ Vγ4+ T cells in local lymphnodes in this psoriasis mouse model. Both, γδ T cells and Th17 cells contributed to IL-17 production in situ and in in vitro restimulation experiments. Injection of diseased CD18hypo PL/J mice with anti-γδTCR-, -IL-17, and -IL-23 antibodies resulted in an almost complete resolution of skin inflammation and eliminated pathological Vγ4+ T cells. In peripheral blood and skin sections from psoriasis patients, we observed a variable increase in IL-17+ gammadelta T cells that correlated with a reduction of CD18 levels compared to age-matched healthy subjects. Conclusion: These results for the first time demonstrate a critical role of skin-infiltrating inflammatory gammadelta T cells in a complex psoriasis model as well as a role for wildtype CD18 expression levels in suppression of pathological gammadelta T cells and suggest the need for individualized therapy of psoriasis patients depending on the skin infiltrate.
IL-17A in Psoriasis and Beyond: Cardiovascular and Metabolic Implications
Frontiers in Immunology
Interleukin 17A (IL-17A) is one of the currently known six members of the IL-17 cytokine family and is implicated in immune responses to infectious pathogens and in the pathogenesis of inflammatory autoimmune diseases like psoriasis. Psoriatic skin is characterized by high expression of IL-17A and IL-17F, which act on immune and non-immune cell types and strongly contribute to tissue inflammation. In psoriatic lesions, IL-17A, IL-17E, and IL-17F are involved in neutrophil accumulation, followed by the formation of epidermal micro abscesses. IL-17A together with other Th17 cytokines also upregulates the production of several chemokines that are implicated in psoriasis pathogenesis. IL17A-targeting antibodies show an impressive clinical efficacy in patients with psoriasis. Studies have reported an improvement of at least 75% as measured by the psoriasis area and severity index (PASI) in >80% of patients treated with anti-IL-17A therapy. Psoriasis skin manifestations, cardiovascular as well as metabolic disease in psoriasis appear to share pathogenic mechanisms evolving around IL-17A and its proinflammatory role. Thus, anti-IL-17A therapy not only improves skin manifestations of psoriasis, but also cardiovascular inflammation as well as metabolic factors and different domains of psoriatic arthritis (PsA) including peripheral arthritis, enthesitis, dactylitis, and axial involvement. This review summarizes the biological role of IL-17A, before reviewing currently available data on its role in the physiology and pathophysiology of the skin, as well as the cardiovascular and the metabolic system. In conclusion, clinical recommendations for patients with moderate to severe psoriasis based on the current available data are given.
The Emerging Role of IL-17 in the Pathogenesis of Psoriasis: Preclinical and Clinical Findings
Journal of Investigative Dermatology, 2013
Abbreviations: AMPs, antimicrobial peptides; mRNA, messenger RNAs; PASI, psoriasis area and severity index; Tc, cytotoxic T; Th1, T-helper 1; TNF-a, tumor necrosis factor-a Chang SH, Dong C (2007) A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses. Cell Res 17:435-40 Chaudhari U, Romano P, Mulcahy LD et al. (2001) Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 357:1842-7 Chen S, Shimada K, Zhang W et al. (2010) IL-17A is proatherogenic in highfat diet-induced and Chlamydia pneumoniae infection-accelerated atherosclerosis in mice. J Immunol 185:5619-27 Chiricozzi A, Guttman-Yassky E, Suarez-Farinas M et al. (2011) Integrative responses to IL-17 and TNF-alpha in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis. J Invest Dermatol 131:677-87 Ciric B, El-behi M, Cabrera R et al. (2009) IL-23 drives pathogenic IL-17producing CD8+ T cells. J Immunol 182:5296-305 Claudio E, Sonder SU, Saret S et al. (2009) The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation.
Experimental Dermatology
Psoriasis is a chronic, immune-mediated, systemic inflammatory disease that is defined by a characteristic skin reaction produced when elevated levels of inflammatory cytokines such as interleukin (IL)-17 alter the growth and differentiation of skin cells. The pathogenesis of comorbid conditions associated with psoriasis, including psoriatic arthritis, cardiovascular disease, obesity, metabolic syndrome, liver disorders, renal disease and depression, is also largely affected by inflammation. In this review, we examine the effect of IL-17 on the inflammatory pathways in a variety of different cell types, including keratinocytes, as well as epithelial cells of the colon, kidney, gut and liver. Additionally, we investigate the role of IL-17 in mediating the psoriasis-associated comorbidities detailed above.
Il-17 and Its Role in Psoriasis, Hidradenitis Suppurativa And Acne
Internal Medicine and Care
Further studies found out that he IL-17 family consists of six members, from IL-17A to IL-17F [4] even if the term IL-17 usually refers to IL-17A [5]. All the family members share some activities: IL-17A, IL-17F and their heterodimers IL-17A/F have inflammatory effect with different strength, IL-17B, IL-17C, IL-17D are proinflammatory with unknown role [6]. The IL-17E cytokine, also named IL-25, is involved in Th2 cells response [7]. In the same way, the receptor family consists of five subunits, from IL-17RA to IL-17RE [7]. All these members have a single transmembrane domain and an extracellular binding domain [6].
Functional Characterization of IL-17F as a Selective Neutrophil Attractant in Psoriasis
Journal of Investigative Dermatology, 2009
IL-17F is known to be involved in many inflammatory diseases, but its role in skin diseases has not been fully examined. Because IL-8 is involved in many skin diseases such as psoriasis, we investigated the production of IL-8 in normal human epidermal keratinocytes (NHEKs) stimulated by IL-17F, tumor necrosis factor-a (TNF-a), IL-17A, and control using real-time PCR and ELISA. The results showed that IL-17F induced production of IL-8 in NHEKs in a time-dependent manner. Interestingly, the amounts of IL-8 stimulated by IL-17F were much higher than those stimulated by TNF-a or IL-17A. Next, we confirmed that selective mitogen-activated protein kinase kinase inhibitors significantly inhibited IL-17F-induced IL-8 production. Moreover, mouse skin intradermally injected with IL-17F expressed high level of IL-8 mRNA and induced ERK1/2 phosphorylation. Histological examination of mouse skin that was injected with IL-17F revealed marked neutrophilia in dermis and the infiltration was significantly inhibited by anti-IL-8 antibody. Finally, IL-17F expression in skin biopsy samples from psoriasis patients were examined by western blotting and ELISA. IL-17F was upregulated in lesional psoriatic skin compared with nonlesional skin. These results indicate that IL-17F may be involved in psoriasis via, in part, the activation of ERK1/2 and the induction of IL-8 in keratinocytes.