Efferocytic remodeling of pancreatic intra-islet macrophages by limited beta-cell death

The primary driver of Type I diabetes are the autoimmune T cells that destroy insulin-producing beta-cells within the islets of Langerhans in the pancreas. Pancreatic macrophages have also been variably linked to disease onset and progression. As macrophage-mediated removal of dying cells via ‘efferocytosis’ regulate tissue homeostasis and immune responses, we addressed whether efferocytosis by intra-islet macrophages influences the immune environment of pancreatic islets. Here, using a series of complementary omics-based and functional approaches, we identify a subset of anti-inflammatory intra-islet ‘efferocytic macrophages’ (e-Mac) within the pancreas of mice and humans. When limited beta-cell apoptosis is induced in vivo in wild type C57BL/6 mice and diabetic-prone NOD mice, islet macrophages adopt this e-Mac phenotype without an apparent increase in total intra-islet macrophage numbers. Strikingly, such induction of limited beta-cell apoptosis and increase in e-Mac numbers in NOD mice led to long-term suppression of autoimmune diabetes. These data advance a concept that efferocytosis-associated reprogramming of the islet macrophages and its subsequent influence on the adaptive immune response could be beneficial in modulating diabetic autoimmunity. sc-RNASeq profiling of CD45+ cells isolated from the islets of non-obese diabetic (NOD) or healthy C57BL/6 mice. Mice were injected with single low-dose STZ (or control buffer) at 4 weeks of age, and analyzed 10 days later (at 5.5 weeks of age) or 8 weeks later (at 12 weeks of age)