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JAK-STAT1作为表皮生长因子受体缺陷相关炎症和瘢痕性脱发的治疗靶点。

JAK-STAT1 as therapeutic target for EGFR deficiency-associated inflammation and scarring alopecia.

作者信息

Strobl Karoline, Klufa Jörg, Jin Regina, Artner-Gent Lena, Krauß Dana, Novoszel Philipp, Strobl Johanna, Stary Georg, Vujic Igor, Griss Johannes, Holcmann Martin, Farlik Matthias, Homey Bernhard, Sibilia Maria, Bauer Thomas

机构信息

Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, 1090, Austria.

Department of Dermatology, Medical University of Vienna, Vienna, 1090, Austria.

出版信息

EMBO Mol Med. 2024 Dec;16(12):3142-3168. doi: 10.1038/s44321-024-00166-3. Epub 2024 Nov 9.

DOI:10.1038/s44321-024-00166-3
PMID:39521937
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11628629/
Abstract

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.

摘要

毛囊干细胞微环境是一种免疫特权微环境，其特征在于抗原呈递减少，从而防止永久性免疫介导的组织损伤。在本研究中，我们证明了毛囊特异性表皮生长因子受体（EGFR）对瘢痕性毛囊破坏的保护作用。从机制上讲，EGFR信号的破坏在JAK-STAT1途径内产生了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，损害了干细胞微环境。在表皮和毛囊特异性EGFR缺失的小鼠模型中，JAK1/2或STAT1的毛囊特异性基因缺失或JAK1/2的治疗性抑制减轻了炎症，恢复了皮肤屏障功能，并激活了残余干细胞以恢复毛发生长。来自EGFR抑制剂治疗的瘢痕性脱发患者的皮肤活检显示，JAK-STAT1信号活跃，同时抗原呈递上调，EGFR途径关键成分下调。我们的研究结果提供了分子见解，并突出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。

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