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

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.

毛囊（Hair follicles, HF）是干细胞、免疫细胞与共生微生物的调控枢纽，在一过性炎症过程中需受到严格调控。事实上，病毒感染后出现的免疫紊乱可诱发自身免疫病或细菌感染。本研究通过构建全身性抗病毒免疫模型，发现I型/III型干扰素应答性毛囊上段中的ADAM10-Notch信号轴（ADAM10-Notch signaling axis）在调控皮肤微生物群、保护毛囊及其干细胞微环境免受炎性破坏中发挥关键作用。抑制ADAM10-Notch信号轴会损伤上皮先天屏障功能，使得棒杆菌属（Corynebacterium）物种成为皮肤微生物群的优势类群。菌群失调会通过依赖IL-7受体、鞘氨醇-1-磷酸受体1及C-C趋化因子受体6（CCR6）的途径，触发2型先天淋巴细胞（group 2 innate lymphoid cells）介导的炎症反应，进而导致毛囊发生焦亡，最终引发不可逆性脱发。综上，在I型/III型干扰素应答过程中，ADAM10-Notch信号轴介导的宿主-微生物共生调控可有效保护毛囊免受炎性破坏，该发现可为慢性炎症状态下维持组织完整性的干预策略提供理论参考。