Bromodomain inhibition instructs macrophages to promote beta cell proliferation and suppress autoimmune diabetes

Abstract

Abstract A hallmark of autoimmune type 1 diabetes (T1D) is the decline of beta cell mass. Any regimen to promote beta cell expansion will have a great therapeutic promise. We have previously demonstrated that an epigenetic inhibitor targeting BET proteins (I-BET) promotes beta cell proliferation in an animal model of T1D. However, the underlying mechanisms remains unknown. Using both gain-of and loss-of function assays, we demonstrate that macrophages play an indispensable role in I-BET-elicited beta cell proliferation. In vivo ablation of macrophages significantly abolishes, while the supplementation of I-BET preconditioned macrophages enhances, I-BET induced beta cell proliferation. On a molecular level, elevated production of platelet-derived growth factor (PDGF) in I-BET treated macrophages mobilizes PDGFR signaling in beta cells. In summary, these findings reveal a novel strategy to expand beta cells by harnessing macrophages.