IL-6 deletion attenuates psoriasis-like skin inflammation in K5-IL-17C mice. (CCR6P.270)

Abstract IL-17C is the most abundant IL-17 family member found in lesional psoriasis skin. IL-17C elicits a 4-fold increase in TNFα (P<0.05) from primary human endothelial cells (ECs) and primary human keratinocytes (KCs) stimulated with IL-17C/TNFα produce synergistic increases in psoriasis signature genes. Mice engineered to overexpress IL-17C in KCs (K5-IL-17C) develop a psoriasiform skin phenotype that improves upon TNFα inhibition. IL-17C also elicits a 3-fold increase in IL-6 from ECs (P<0.05), and IL-6 protein levels significantly increase in uninvolved and involved skin of K5-IL-17C mice (42% and 480%; P<0.05). We hypothesized that IL-6 synergizes with IL-17C to elicit chronic skin inflammation, akin to IL-17C/TNFα. To test this, we mated K5-IL-17C mice with IL-6 KO mice. K5-IL-17C-IL-6 KO mice develop less severe skin disease at 8-10 weeks of age vs K5-IL-17C mice (40% decrease in mouse PASI; n=15, P<0.05) and have significant decreases in serum TNFα (64%; n=4; P<0.035). Histological analyses of involved skin show no differences between K5-IL-17C vs K5-IL-17C-IL-6 KO mice, however analyses of uninvolved skin reveal a significantly thinner epidermis (2-fold decrease; P<0.001), decrease in dermal angiogenesis (27%; P<0.04), and decreases in CD4+ and CD8+ T cells and F4/80+ macrophages (30-51%; P<0.05) in K5-IL-17C-IL-6 KO vs K5-IL-17C mice (n=8/group). These data suggest that IL-6 may contribute to proinflammatory IL-17C signaling critical for sustained psoriasis pathogenesis.