Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH.
Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
J Exp Med. 2019 Jan 7;216(1):195-214. doi: 10.1084/jem.20171849. Epub 2018 Dec 21.
Lrig1 marks a distinct population of stem cells restricted to the upper pilosebaceous unit in normal epidermis. Here we report that IL-17A-mediated activation of EGFR plays a critical role in the expansion and migration of Lrig1 stem cells and their progenies in response to wounding, thereby promoting wound healing and skin tumorigenesis. Lrig1-specific deletion of the IL-17R adaptor Act1 or EGFR in mice impairs wound healing and reduces tumor formation. Mechanistically, IL-17R recruits EGFR for IL-17A-mediated signaling in Lrig1 stem cells. While TRAF4, enriched in Lrig1 stem cells, tethers IL-17RA and EGFR, Act1 recruits c-Src for IL-17A-induced EGFR transactivation and downstream activation of ERK5, which promotes the expansion and migration of Lrig1 stem cells. This study demonstrates that IL-17A activates the IL-17R-EGFR axis in Lrig1 stem cells linking wound healing to tumorigenesis.
Lrig1 标记了正常表皮中毛囊皮脂腺单元中一个独特的干细胞群体。在这里，我们报告 IL-17A 介导的 EGFR 激活在创伤反应中对于 Lrig1 干细胞及其祖细胞的扩增和迁移起着关键作用，从而促进伤口愈合和皮肤肿瘤发生。在小鼠中 Lrig1 特异性缺失 IL-17R 衔接蛋白 Act1 或 EGFR 会损害伤口愈合并减少肿瘤形成。在机制上，IL-17R 将 EGFR 募集到 Lrig1 干细胞中的 IL-17A 介导的信号转导中。虽然 TRAF4 在 Lrig1 干细胞中富集，但它将 IL-17RA 和 EGFR 连接在一起，Act1 将 c-Src 募集到 IL-17A 诱导的 EGFR 转位激活和 ERK5 的下游激活，从而促进 Lrig1 干细胞的扩增和迁移。这项研究表明，IL-17A 在 Lrig1 干细胞中激活 IL-17R-EGFR 轴，将伤口愈合与肿瘤发生联系起来。
