The Journal of investigative dermatology | 2021
IL-6R/STAT3-signaling in keratinocytes rather than T cells induces psoriasis-like dermatitis in mice.
Abstract
STAT3 is important for psoriasis pathogenesis as STAT3-signaling downstream of IL-6, IL-21, IL-22 and IL-23 contributes to Th17 cell development and keratinocyte STAT3 expression in transgenic mice (K14-Stat3C mice) develop psoriasis-like dermatitis. Herein, the relative contribution of STAT3-signaling in keratinocytes versus T cells was evaluated in the imiquimod model of psoriasis-like dermatitis. Mice with STAT3 inducible deletion in keratinocytes (K5-STAT3-/- mice) had decreased psoriasis-like dermatitis and epidermal phosphorylation of STAT3 (pSTAT3) compared with wt mice, whereas mice with constitutive deletion of STAT3 in all T cells were like wt mice. Interestingly, mice with keratinocyte-inducible deletion of IL-6 receptor alpha had similar findings as K5-STAT3-/- mice, identifying IL-6/IL-6R as a predominant upstream signal for keratinocyte-STAT3-induced psoriasis-like dermatitis. Moreover, psoriasis-like dermatitis inversely associated with type 1 immune gene products, especially CXCL10, whereas CXCL10 limited psoriasis-like dermatitis, suggesting that keratinocyte-STAT3 signaling promoted psoriasis-like dermatitis by restricting downstream CXCL10 expression. Finally, treatment of mice with the pan-JAK inhibitor, tofacitinib reduced psoriasis-like dermatitis and epidermal pSTAT3 expression. Taken together, STAT3-signaling in keratinocytes rather than T cells was a more important determinant for psoriasis-like dermatitis in a mechanism that involved upstream keratinocyte IL-6R-signaling and downstream inhibition of type 1 immunity-associated CXCL10 responses.