The hair follicle stem cell niche is an immune-privileged microenvironment, characterized by reduced antigen presentation, thus shielding against permanent immune-mediated tissue damage. In this study, we demonstrated the protective role of hair follicle-specific epidermal growth factor receptor (EGFR) against scarring hair follicle destruction. Mechanistically, disruption of EGFR signaling generated a cell-intrinsic hypersensitivity within the JAK-STAT1 pathway, which, synergistically with interferon gamma expressing CD8 T-cell and NK-cell-mediated inflammation, compromised the stem cell niche. Hair follicle-specific genetic depletion of either JAK1/2 or STAT1 or therapeutic inhibition of JAK1/2 ameliorated the inflammation, restored skin barrier function and activated the residual stem cells to resume hair growth in mouse models of epidermal and hair follicle-specific EGFR deletion. Skin biopsies from EGFR inhibitor-treated and cicatricial alopecia patients revealed an active JAK-STAT1 signaling signature along with upregulation of antigen presentation and downregulation of key components of the EGFR pathway. Our findings offer molecular insights and highlight a mechanism-based therapeutic strategy for addressing chronic folliculitis associated with EGFR-inhibitor anti-cancer therapy and cicatricial alopecia.

中文翻译：

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JAK-STAT1 作为 EGFR 缺陷相关炎症和瘢痕性脱发的治疗靶点。


毛囊干细胞生态位是一种免疫特权微环境，其特征是抗原呈递减少，从而抵御永久性免疫介导的组织损伤。在这项研究中，我们证明了毛囊特异性表皮生长因子受体 （EGFR） 对疤痕毛囊破坏的保护作用。从机制上讲，EGFR 信号传导的破坏在 JAK-STAT1 通路内产生细胞内在的超敏反应，这与表达干扰素 γ 的 CD8 T 细胞和 NK 细胞介导的炎症协同作用，损害了干细胞生态位。JAK1/2 或 STAT1 的毛囊特异性基因耗竭或 JAK1/2 的治疗性抑制改善了炎症，恢复了皮肤屏障功能并激活了残留的干细胞，以恢复表皮和毛囊特异性 EGFR 缺失小鼠模型中的毛发生长。EGFR 抑制剂治疗和瘢痕性脱发患者的皮肤活检显示活性 JAK-STAT1 信号转导特征以及抗原呈递的上调和 EGFR 通路关键成分的下调。我们的研究结果提供了分子见解，并强调了一种基于机制的治疗策略，用于解决与 EGFR 抑制剂抗癌治疗和瘢痕性脱发相关的慢性毛囊炎。