Stress-induced β cell early senescence confers protection against type 1 diabetes
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
Abstract
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.