Staphylococcus aureus Epicutaneous Exposure Drives Skin Inflammation via IL-36-Mediated T Cell Responses

Abstract

Staphylococcus aureus colonization contributes to skin inflammation in diseases such as atopic dermatitis, but the signaling pathways involved are unclear. Herein, epicutaneous S.aureus exposure to mouse skin promoted MyD88-dependent skin inflammation initiated by IL-36, but not IL-1α/β, IL-18, or IL-33. By contrast, an intradermal S.aureus challenge promoted MyD88-dependent host defense initiated by IL-1β rather than IL-36, suggesting that different IL-1 cytokines trigger MyD88 signaling depending on the anatomical depth of S.aureus cutaneous exposure. The bacterial virulence factor PSMα, but not α-toxin or δ-toxin, contributed to the skin inflammation, which was driven by IL-17-producing γδ andCD4+ Tcells via direct IL-36R signaling in the Tcells. Finally, adoptive transfer of IL-36R-expressing Tcells to IL-36R-deficient mice was sufficient for mediating S.aureus-induced skin inflammation. Together, this study defines a previously unknown pathway by which S.aureus epicutaneous exposurepromotes skin inflammation involving IL-36R/MyD88-dependent IL-17 Tcell responses.