Keratinocyte overexpression of IL-17C promotes psoriasiform skin inflammation.
IL-17C is a functionally distinct member of the IL-17 family that binds IL-17 receptor E/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 (1058 versus 8 pg/ml; p < 0.006) and localizes to keratinocytes (KCs), endothelial cells (ECs), and leukocytes. ECs stimulated with IL-17C produce increased TNF-α and KCs stimulated with IL-17C/TNF-α produce similar inflammatory gene response patterns as those elicited by IL-17A/TNF-α, including increases in IL-17C, TNF-α, IL-8, IL-1α/β, IL-1F5, IL-1F9, IL-6, IL-19, CCL20, S100A7/A8/A9, DEFB4, lipocalin 2, and peptidase inhibitor 3 (p < 0.05), indicating a positive proinflammatory feedback loop between the epidermis and ECs. Psoriasis patients treated with etanercept rapidly decrease cutaneous IL-17C levels, suggesting IL-17C/TNF-α-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/A9 expression (p < 0.05) but no epidermal hyperplasia, whereas involved skin exhibits robust epidermal hyperplasia, increased angiogenesis and leukocyte infiltration, and upregulated TNF-α, IL-1α/β, IL-17A/F, IL-23p19, vascular endothelial growth factor, IL-6, and CCL20 (p < 0.05), suggesting that IL-17C, when coupled with other proinflammatory signals, initiates the development of psoriasiform dermatitis. This skin phenotype was significantly improved following 8 wk of TNF-α 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.
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA.
Andrew
A
Johnston
Yi
Y
Fritz
Sean M
SM
Dawes
Doina
D
Diaconu
Paul M
PM
Al-Attar
Andrew M
AM
Guzman
Cynthia S
CS
Chen
Wen
W
Fu
Johann E
JE
Gudjonsson
Thomas S
TS
McCormick
Nicole L
NL
Ward
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000068800:Etanercept; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D061251:Primary Cell Culture; D011565:Psoriasis / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; C508717:IL17A protein, human; D007074:Immunoglobulin G; D020381:Interleukin-17; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept