Apoptotic β-cells induce macrophage reprogramming under diabetic conditions

Type 2 diabetes mellitus (T2DM) occurs when insulin-producing pancreatic β-cells fail to secrete sufficient insulin to compensate for insulin resistance. As T2DM progresses, apoptotic β-cells need to be removed by macrophages through efferocytosis that is anti-inflammatory by nature. Paradoxically, infiltrating macrophages are a main source of inflammatory cytokines that leads to T2DM. It is unclear how apoptotic β-cells impact macrophage function. We show under diabetic conditions, phagocytosis of apoptotic β-cells causes lysosomal permeabilization and generates reactive oxygen species that lead to inflammasome activation and cytokine secretion in macrophages. Efferocytosis-induced lipid accumulation transforms islet macrophages into foam cell-like outside the context of atherosclerosis. Our study suggests that whereas macrophages normally play a protective anti-inflammatory role, the increasing demand of clearing apoptotic cells may trigger them to undergo proinflammatory reprogramming as T2DM progresses. This shift in the balance between opposing macrophage inflammatory responses could contribute to chronic inflammation involved in metabolic diseases. Our study highlights the importance of preserving macrophage lysosomal function as a therapeutic intervention for diabetes progression.