IL-6R/Signal Transducer and Activator of Transcription 3 Signaling in Keratinocytes rather than in T Cells Induces Psoriasis-Like Dermatitis in Mice.

The Journal of investigative dermatology 2022 Apr

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Signal transducer and activator of transcription 3 (STAT3) is important for psoriasis pathogenesis because STAT3 signaling downstream of IL-6, IL-21, IL-22, and IL-23 contributes to T helper type 17 cell development and because transgenic mice with keratinocyte (KC) STAT3 expression (K14-Stat3C mice) develop psoriasis-like dermatitis. In this study, the relative contribution of STAT3 signaling in KCs versus in T cells was evaluated in the imiquimod model of psoriasis-like dermatitis. Mice with STAT3-inducible deletion in KCs (K5-Stat3-/- mice) had decreased psoriasis-like dermatitis and epidermal STAT3 phosphorylation compared with wild-type mice, whereas mice with constitutive deletion of STAT3 in all T cells were similar to wild-type mice. Interestingly, mice with KC-inducible deletion of IL-6Rα had similar findings to those of K5-Stat3-/- mice, identifying IL-6/IL-6R as a predominant upstream signal for KC 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 KC 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 STAT3 phosphorylation. Taken together, STAT3 signaling in KCs rather than in T cells was a more important determinant for psoriasis-like dermatitis in a mechanism that involved upstream KC IL-6R signaling and downstream inhibition of type 1 immunity‒associated CXCL10 responses. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Advaitaa Ravipati, Sabrina Nolan, Martin Alphonse, Dustin Dikeman, Christine Youn, Yu Wang, Nicholas Orlando, Garrett Patrick, Steven Lee, Roger V Ortines, Haiyun Liu, Robert J Miller, Carly A Dillen, Mark Marchitto, S Sarah Cai, Lloyd S Miller, Nathan K Archer. IL-6R/Signal Transducer and Activator of Transcription 3 Signaling in Keratinocytes rather than in T Cells Induces Psoriasis-Like Dermatitis in Mice. The Journal of investigative dermatology. 2022 Apr;142(4):1126-1135.e4