Macrophages and neutrophils are necessary for ER stress-induced β cell loss.

Persistent endoplasmic reticulum (ER) stress induces islet inflammation and β cell loss. How islet inflammation contributes to β cell loss remains uncertain. We have reported previously that chronic overnutrition-induced ER stress in β cells causes Ripk3-mediated islet inflammation, macrophage recruitment, and a reduction of β cell numbers in a zebrafish model. We show here that β cell loss results from the intricate communications among β cells, macrophages, and neutrophils. Macrophage-derived Tnfa induces cxcl8a in β cells. Cxcl8a, in turn, attracts neutrophils to macrophage-contacted "hotspots" where β cell loss occurs. We also show potentiation of chemokine expression in stressed mammalian β cells by macrophage-derived TNFA. In Akita and db/db mice, there is an increase in CXCL15-positive β cells and intra-islet neutrophils. Blocking neutrophil recruitment in Akita mice preserves β cell mass and slows diabetes progression. These results reveal an important role of neutrophils in persistent ER stress-induced β cell loss.