Skin/gut microbiome from WT, ADAM10Mx1, RBPJMx1, and ADAM10Mx1 Ccr6KO. Raw sequence reads

Hair follicles (HF) function as hubs for stem cells, immune cells, and commensal microbes, which must be tightly regulated during transient inflammation. Indeed, perturbed immunity post-viral infections can precipitate autoimmune diseases or bacterial infections. Herein, we utilized a model of systemic anti-viral immunity and found that the ADAM10-Notch signaling axis in type I/III interferon-responsive upper HFs was crucial for regulating skin microbiota and protecting HFs and its stem cell niche from inflammatory destruction. Inhibition of ADAM10-Notch signaling axis impaired innate epithelial barrier that enabled Corynebacterium species to predominate the microbiome. Dysbiosis triggered group 2 innate lymphoid cells-mediated inflammation in IL-7 receptor-, sphingosine-1-phosphate receptor 1- and CCR6-dependent manners, leading to pyroptotic cell death of HFs, resulting in irreversible alopecia. Thus, ADAM10-Notch signaling axis-mediated regulation of host-microbial symbiosis during a type I/III interferon response crucially protects HFs from inflammatory destruction, which has implications for strategies to sustain tissue integrity during chronic inflammation.