| First Author | Lee H | Year | 2023 |
| Journal | Cell Metab | Volume | 35 |
| Issue | 12 | Pages | 2200-2215.e9 |
| PubMed ID | 37949065 | Mgi Jnum | J:343574 |
| Mgi Id | MGI:7565204 | Doi | 10.1016/j.cmet.2023.10.014 |
| Citation | Lee H, et al. (2023) Stress-induced beta cell early senescence confers protection against type 1 diabetes. Cell Metab 35(12):2200-2215.e9 |
| abstractText | During the progression of type 1 diabetes (T1D), beta cells are exposed to significant stress and, therefore, require adaptive responses to survive. The adaptive mechanisms that can preserve beta cell function and survival in the face of autoimmunity remain unclear. Here, we show that the deletion of the unfolded protein response (UPR) genes Atf6alpha or Ire1alpha in beta cells of non-obese diabetic (NOD) mice prior to insulitis generates a p21-driven early senescence phenotype and alters the beta 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 beta cells, the reduction of beta cell apoptosis, and protection against T1D. We further demonstrate that the p21-mediated early senescence signature is conserved in the residual beta cells of T1D patients. Our findings reveal a previously unrecognized link between beta cell UPR and senescence that, if leveraged, may represent a novel preventive strategy for T1D. |
