Keratinocyte IL-36 Receptor/MyD88 Signaling Mediates Malassezia-Induced IL-17-Dependent Skin Inflammation

Background. Among skin commensal fungi, lipophilic Malassezia species exist on nearly all human skin surfaces. The pathophysiology of Malassezia-associated skin diseases remains poorly understood due in part to the lack of appropriate animal models. Our objective was to investigate the mechanisms underlying Malassezia-induced skin inflammation using a novel murine model that physiologically recapitulates Malassezia skin infection. Methods. Mice were inoculated epicutaneously with Malassezia yeasts without barrier disruption and in the absence of external lipid supplementation. Skin inflammation, lesional fungal loads, and expression of cytokines and antimicrobial peptides were evaluated in wild-type and mutant mouse strains. Results. Malassezia-induced skin inflammation and epidermal thickening were observed on day 4 after inoculation in wild-type mice. High fungal burdens were detected in the cornified layer on day 2 and decreased thereafter with near complete clearance by day 7 after inoculation. Malassezia-induced skin inflammation and fungal clearance by the host were interleukin-17 (IL-17) dependent with contribution of group 3 innate lymphoid cells. Moreover, IL-17-dependent skin inflammation was mediated through IL-36 receptor and keratinocyte MyD88 signaling. Conclusion. Using a new skin infection model, it is shown that Malassezia-induced IL-17- dependent skin inflammation and control of fungal infection are mediated via keratinocyte IL-36 receptor/MyD88 signaling.