Keratinocyte Overexpression of IL-17C Promotes Psoriasiform Skin Inflammation

Abstract

IL-17C is a functionally distinct member of the IL-17 family that binds IL-17RE/A to promote innate defense in epithelial cells and regulate Th17 cell differentiation. We demonstrate that IL-17C (not IL-17A) is the most abundant IL-17 isoform in lesional psoriasis skin (1058pg/ml vs. 8pg/ml; p<0.006) and localizes to keratinocytes (KCs), endothelial cells (ECs) and leukocytes. ECs stimulated with IL-17C produce increased TNFα and KCs stimulated with IL-17C/TNFα produce similar inflammatory gene response patterns as those elicited by IL-17A/TNFα, including increases in IL-17C, TNFα, IL-8, IL-1α/β, IL-1F5, IL-1F9, IL-6, IL-19, CCL20, S100A7/A8/A9, DEFB4, LCN2 and PI3 (p<0.05); indicating a positive pro-inflammatory feedback loop between the epidermis and ECs. Psoriasis patients treated with etanercept rapidly decrease cutaneous IL-17C levels, suggesting IL-17C/TNFα-mediated inflammatory signaling is critical for psoriasis pathogenesis. Mice genetically engineered to overexpress IL-17C in KCs develop well-demarcated areas of erythematous, flakey “involved” skin adjacent to areas of normal appearing “uninvolved” skin despite increased IL-17C expression in both areas (p<0.05). Uninvolved skin displays increased angiogenesis and elevated S100A8/A9expression (p<0.05) but no epidermal hyperplasia; whereas involved skin exhibits robust epidermal hyperplasia, increased angiogenesis and leukocyte infiltration and upregulated TNFα, IL-1α/β, IL-17A/F, IL-23p19, VEGF, IL-6 and CCL20 (p<0.05) suggesting that IL-17C, when coupled with other pro-inflammatory signals, initiates the development of psoriasiform dermatitis. This skin phenotype was significantly improved following 8 weeks of TNFα inhibition. These findings identify a role for IL-17C in skin inflammation and suggest a pathogenic function for the elevated IL-17C observed in lesional psoriasis skin.

The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity

“…Both IL-17 and IL-17F are highly elevated in skin biopsies from psoriasis patients. 19,96,97 Similar to IBD, GWAS data from psoriasis specimens show that IL-23R and Act1 are psoriasis-associated genes. [98][99][100] In mice, intracutaneous injection of IL-23 causes psoriasis-like epidermal hyperplasia; this skin inflammation is ameliorated in Il17a-, Il17ra-or Il22-deficient mice.…”

“…96 IL-17C targets human primary epidermal keratinocytes to induce inflammatory gene and antibacterial peptide expression from these cells. 19,26 IL-17C also synergistically cooperates with other inflammatory cytokines (that is, TNFα or IL-1β) to amplify the expression of psoriasis-related genes in keratinocytes. 19,26 In addition to keratinocytes, IL-17C triggers inflammatory gene production in human dermal microvascular endothelial cells.…”

“…19,26 IL-17C also synergistically cooperates with other inflammatory cytokines (that is, TNFα or IL-1β) to amplify the expression of psoriasis-related genes in keratinocytes. 19,26 In addition to keratinocytes, IL-17C triggers inflammatory gene production in human dermal microvascular endothelial cells. 19 In contrast to the protective roles of IL-17C in colitis models, IL-17C signaling aggravates the pathogenesis of several psoriatic models in mice.…”

“…IL-17C mRNA is also found in endothelial cells and leukocytes, but the function of IL-17C in these cells is poorly understood. 10,19 IL-17E-producing cells are more diverse than the cells that produce IL-17C and include Th2 cells, eosinophils, basophils, alveolar macrophages, microglia, IgE-activated mast cells, epithelial cells and endothelial cells. 9 IL-17E-producing cells are related to type 2 immunity.…”

“…61,66 The ectopic expression of IL-17C in vivo by different methodologies also causes inflammatory responses in the lungs, joints and skin. 19,61,67 Mechanistically, IL-17C binds to the IL-17RE-IL-17RA receptor complex to induce downstream signaling pathway activation. In contrast to the universal expression of IL-17RA, IL-17RE is mainly located on epithelial cells, keratinocytes or Th17 cells.…”