衰老
生物
炎症
未折叠蛋白反应
细胞生物学
小岛
胰岛炎
自身免疫
免疫系统
免疫学
癌症研究
表型
点头老鼠
细胞
电池类型
糖尿病
基因
遗传学
内质网
内分泌学
作者
Hugo Lee,Gulcan Semra Sahin,Chien-Wen Chen,Shreyash Sonthalia,Sandra Marín Cañas,Hülya Zeynep Oktay,Alexander T. Duckworth,Gabriel Brawerman,Peter J. Thompson,Maria Hatzoglou,Décio L. Eizirik,Feyza Engin
出处
期刊:Cell Metabolism
[Elsevier]
日期:2023-12-01
卷期号:35 (12): 2200-2215.e9
被引量:11
标识
DOI:10.1016/j.cmet.2023.10.014
摘要
During the progression of type 1 diabetes (T1D), β cells are exposed to significant stress and, therefore, require adaptive responses to survive. The adaptive mechanisms that can preserve β cell function and survival in the face of autoimmunity remain unclear. Here, we show that the deletion of the unfolded protein response (UPR) genes Atf6α or Ire1α in β cells of non-obese diabetic (NOD) mice prior to insulitis generates a p21-driven early senescence phenotype and alters the β cell secretome that significantly enhances the leukemia inhibitory factor-mediated recruitment of M2 macrophages to islets. Consequently, M2 macrophages promote anti-inflammatory responses and immune surveillance that cause the resolution of islet inflammation, the removal of terminally senesced β cells, the reduction of β cell apoptosis, and protection against T1D. We further demonstrate that the p21-mediated early senescence signature is conserved in the residual β cells of T1D patients. Our findings reveal a previously unrecognized link between β cell UPR and senescence that, if leveraged, may represent a novel preventive strategy for T1D.
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