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Early senescence-induced immunosuppressive β-cell secretome prevents type 1 diabetes

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 deletion of the unfolded protein response genes, Atf6α or Ire1α, in β-cells of NOD mice prior to insulitis generates a p21-driven early senescence phenotype and altered β-cell secretome that significantly enhances leukemia inhibitory factor-mediated recruitment of M2 macrophages to the islets. Consequently, M2 macrophages promote anti-inflammatory responses and immune surveillance that cause resolution of islet inflammation, removal of terminally senesced β-cells, reduction of β-cell apoptosis, and prevention of T1D. We further demonstrate that p21-mediated early senescence signature is conserved in 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 therapeutic strategy for T1D.

ORGANISM(S): Mus musculus

PROVIDER: GSE239947 | GEO | 2023/11/20

REPOSITORIES: GEO

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