Interleukin-17 alters the biology of many cell types involved in the genesis of psoriasis, systemic inflammation and associated comorbidities (original) (raw)
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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.
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.)
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.
IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms
Proceedings of the National Academy of Sciences of the United States of America, 2014
Psoriasis is a chronic inflammatory skin disease characterized by abnormal keratinocyte proliferation and differentiation and by an influx of inflammatory cells. The mechanisms underlying psoriasis in humans and in mouse models are poorly understood, although evidence strongly points to crucial contributions of IL-17 cytokines, which signal via the obligatory adaptor CIKS/Act1. Here we identify critical roles of CIKS/Act1-mediated signaling in imiquimod-induced psoriatic inflammation, a mouse model that shares features with the human disease. We found that IL-17 cytokines/CIKS-mediated signaling into keratinocytes is essential for neutrophilic microabscess formation and contributes to hyperproliferation and markedly attenuated differentiation of keratinocytes, at least in part via direct effects. In contrast, IL-17 cytokines/CIKS-mediated signaling into nonkeratinocytes, particularly into dermal fibroblasts, promotes cellular infiltration and, importantly, leads to enhanced the accu...
Life
Interleukin 17 (IL-17) is an effector cytokine that plays a key role in the pathogenesis of both psoriasis and metabolic-associated fatty liver disease (MAFLD), a condition that is more prevalent and severe in patients with psoriasis. In liver inflammation, IL-17 is mainly produced by CD4+ T (TH17) and CD8+ T cells (Tc17), although numerous other cells (macrophages, natural killer cells, neutrophils and Tγδ cells) also contribute to the production of IL-17. In hepatocytes, IL-17 mediates systemic inflammation and the recruitment of inflammatory cells to the liver, and it is also implicated in the development of fibrosis and insulin resistance. IL-17 levels have been correlated with progression from MAFLD to steatohepatitis, cirrhosis, and even hepatocellular carcinoma. Clinical trials have shown that inhibiting IL-17A in patients with psoriasis could potentially contribute to the improvement of metabolic and liver parameters. A better understanding of the key factors involved in the...
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.
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.
Involvement of IL-17F via the induction of IL-6 in psoriasis
Archives of Dermatological Research, 2010
Recently, the important role of T helper 17 (Th17) cells in psoriasis has been clariWed; however, the role of IL-17F produced by Th17 cells is still not fully understood. IL-6 exhibits multiple biologic functions, such as regulation of immunological responses including those in psoriatic reactions. Therefore, we examined the production of IL-6 protein in normal human epidermal keratinocytes (NHEKs) stimulated by IL-17F, TNF-, IL-17A, and IL-17A in combination with TNF-, and PBS control. We then examined the expression of IL-6 mRNA in mouse skin after intradermal injection of IL-17F. Finally, IL-17F expression in skin biopsy specimens from psoriasis patients was examined by immunohistochemistry. The results showed that IL-17F induced production of IL-6 in NHEKs in a time-dependent manner. This could be attenuated by chimeric inhibitor blocking the IL-17 receptor. The amounts of IL-6 stimulated by IL-17F were much higher than those stimulated by TNF-or IL-17A. IL-6 was also signiWcantly upregulated via synergistic stimulation with IL-17A plus TNF-. The expression of IL-6 mRNA 24 h after IL-17F injection in the mouse skin was 3.2-fold higher than that in the control group. Immunohistochemistry of inXammatory cells in the dermis demonstrated a large number of CD4 + T cells showing IL-17F positivity in psoriatic skin lesions, but few or none in non-lesional psoriatic skin. Our results indicate that IL-17F produced by CD4 + T cells causes the inXammation in psoriasis partly through induction of IL-6 in keratinocytes.