MyD88 restricts dysbiosis-mediated inflammation in filaggrin deficient skin.

Abstract

Atopic dermatitis (AD) is a common inflammatory skin disease associated with epidermal barrier dysfunction, immune dysregulation, and microbial dysbiosis. Loss-of-function mutations in filaggrin, a critical epidermal protein, represent the strongest genetic risk factor for AD and result in compromised skin barrier integrity and altered immune responses. MyD88 is an adaptor protein essential for TLR and IL-1 receptor signaling, with dual roles in promoting inflammation and regulating immune tolerance. However, the function of MyD88 in maintaining skin homeostasis in the context of filaggrin deficiency remains unclear. Here, we used filaggrin-deficient (ft/ft) mice crossed with MyD88 knockout mice (ft/ftMyD88-/-) to investigate the immunological and microbial consequences of MyD88 signaling. In wildtype and ft/ft mice, MyD88 was predominantly expressed in skin epithelia during homeostasis, whereas ft/ftMyD88-/- mice developed spontaneous periocular skin inflammation. RNA-seq revealed upregulation of the IL-17 pathway in ft/ftMyD88-/- inflamed skin. Flow cytometry identified Vγ4 ⁺ γδ T cells as the major source of IL-17A in ft/ftMyD88-/- inflamed skin. We also discovered that ft/ftMyD88-/- skin inflammation was associated with markedly downregulated lipid metabolism genes as well as sebaceous gland abnormalities histologically. Moreover, 16S rRNA gene sequencing demonstrated microbial dysbiosis in ft/ft MyD88-/- periocular skin, which drove skin inflammation as well as IL-17-producing γδ T cell infiltration. Our findings indicate a role for MyD88 in homeostatic control of sebaceous glands and suppression of dysbiosis-driven IL-17A-mediated inflammation in filaggrin-deficient skin. These insights advance our understanding of AD pathogenesis and may offer novel therapeutic strategies for patients with filaggrin mutations.