629 Staphylococcus aureus drives atopic dermatitis-like skin inflammation via IL-36-induced IL-17 responses

Staphylococcus aureus colonization and impetiginization is associated with atopic dermatitis (AD) in humans. However, the precise immune responses induced by S. aureus that contribute to AD pathogenesis and flares are not entirely clear. Herein, we show that epicutaneous application of S. aureus to mouse skin resulted in AD-like skin inflammation with increased epidermal thickness, serum IgE levels, and IL-17/IL-22 responses. Interestingly, the S. aureus-induced AD-like skin inflammation and increased IgE levels were markedly attenuated in MyD88-deficient mice. Of the known MyD88-dependent cytokines, the skin inflammation was similarly attenuated in IL-36R-deficient mice but not in IL-1α or IL-1β-deficient mice. Using cre/lox conditional deletion of MyD88 in specific cell types, the S. aureus-induced skin inflammation was dependent on MyD88 expression by T cells but not keratinocytes or myeloid cells. Further, MyD88 and IL 36R-deficient mice had diminished IL-17/IL-22 levels in the skin and IL-17/IL-22-producing CD4+ and γδ T cells in the draining lymph nodes whereas Th1 and Th2 associated cytokines in the skin were not markedly different compared with wildtype mice. Furthermore, mice deficient in IL-17A/F but not IL-22 had reduced skin inflammation and serum IgE levels to levels observed in MyD88 and IL36R-deficient mice. Finally, exogenous IL-36α in conjunction with heat-killed S. aureus in vitro directly enhanced the survival of CD4+ and γδ T cells and IL-17A production by γδ T cells. Taken together, S. aureus-mediated AD-like skin inflammation and IgE production is mediated by IL-36R/MyD88-dependent T cell-induced IL-17 responses.