Interleukin-17A and Keratinocytes in Psoriasis

Abstract

The excellent clinical efficacy of anti-interleukin 17A (IL-17A) biologics on psoriasis indicates a crucial pathogenic role of IL-17A in this autoinflammatory skin disease. IL-17A accelerates the proliferation of epidermal keratinocytes. Keratinocytes produce a myriad of antimicrobial peptides and chemokines, such as CXCL1, CXCL2, CXCL8, and CCL20. Antimicrobial peptides enhance skin inflammation. IL-17A is capable of upregulating the production of these chemokines and antimicrobial peptides in keratinocytes. CXCL1, CXCL2, and CXCL8 recruit neutrophils and CCL20 chemoattracts IL-17A-producing CCR6⁺ immune cells, which further contributes to forming an IL-17A-rich milieu. This feed-forward pathogenic process results in characteristic histopathological features, such as epidermal hyperproliferation, intraepidermal neutrophilic microabscess, and dermal CCR6⁺ cell infiltration. In this review, we focus on IL-17A and keratinocyte interaction regarding psoriasis pathogenesis.

Keywords: CCL20; CXCL1; CXCL8; ILC3; Koebner phenomenon; Th17; antimicrobial peptides; interleukin-17A; keratinocytes; psoriasis.

Figure 1

Simplified effects of anti-interleukin 17A (IL-17A) on keratinocyte (KC) with regard to psoriasis pathogenesis. IL-17A homodimers bind to IL-17 receptor A (IL-17RA) and IL-17RC or IL-17RA and IL-17RD heterodimers. The ligation of IL-17RA/IL-17RC activates epidermal growth factor receptor (EGFR) directly or by transforming growth factor-α (TGF-α) and heparin-binding EGF-like growth factor (HB-EGF) and promotes keratinocyte proliferation. The ligation of IL-17RA/IL-17RC activates various signal transduction molecules, including ERK, p38 MAPK, JNK, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), IκBζ, C/CAAT-enhancer-binding protein β (C/EBPβ), and C/EBPδ. In contrast, the ligation of IL-17RA/IL-17RD preferentially activates JNK and p38 MAPK pathways. IL-17RA/IL-17RD is estimated to transactivate fibroblast growth factor receptor (FGFR); however, this is not conclusive. IL-17RA/IL-17RC signaling stimulates KCs to produce IL-19, which induces the production of keratinocyte growth factor (KGF) from fibroblasts. KGF also enhances the proliferation of KCs. IL-17A also induces the production of antimicrobial peptides, including S100A7, S100A8, S100A9, LL-37, and defensin β 4A (DEFB4A). These antimicrobial peptides amplify the local inflammatory process. Chemokines, such as CCL20, CXCL1, and CXCL8, are also produced from keratinocytes by IL-17RA/IL-17RC ligation. CCL20 is a key chemokine for the recruitment of CCR6⁺ Th17 cells and group 3 innate lymphoid cells (ILC3). These CCR6⁺ cells produce large amounts of IL-17A. DEFB4A also exhibits a chemotactic activity by binding to CCR6. CXCL1 and CXCL2 are potent chemoattractants for CXCR2⁺ neutrophils. Therefore, IL-17A is associated with all of the histopathologic features of psoriasis.

Figure 2

Pivotal role of signal transducer and activator of transcription 3 (STAT3) in psoriasis. The activation of STAT3 promotes keratinocyte (KC) proliferation and inflammatory response. IL-17A and IL-22 induce the STAT3 activation. IL-6 produced from KC also induces STAT3 activation.