Pancreatic-islet inflammation contributes to the failure of β cell insulin secretion during obesity and type 2 diabetes. However, little is known about the nature and function of resident immune cells in this context or in homeostasis. Here we show that interleukin (IL)-33 was produced by islet mesenchymal cells and enhanced by a diabetes milieu (glucose, IL-1β, and palmitate). IL-33 promoted β cell function through islet-resident group 2 innate lymphoid cells (ILC2s) that elicited retinoic acid (RA)-producing capacities in macrophages and dendritic cells via the secretion of IL-13 and colony-stimulating factor 2. In turn, local RA signaled to the β cells to increase insulin secretion. This IL-33-ILC2 axis was activated after acute β cell stress but was defective during chronic obesity. Accordingly, IL-33 injections rescued islet function in obese mice. Our findings provide evidence that an immunometabolic crosstalk between islet-derived IL-33, ILC2s, and myeloid cells fosters insulin secretion.

肥胖和2型糖尿病期间，胰岛炎症会导致β细胞胰岛素分泌失败。然而，关于这种情况或体内稳态中的驻留免疫细胞的性质和功能了解甚少。在这里，我们显示白介素（IL）-33由胰岛间充质细胞产生，并由糖尿病环境（葡萄糖，IL-1β和棕榈酸酯）增强。IL-33通过胰岛驻留的第2组先天性淋巴样细胞（ILC2s）促进β细胞功能，该细胞通过IL-13和集落刺激因子2的分泌引发巨噬细胞和树突状细胞中视黄酸（RA）的生产能力。 ，局部RA向β细胞发出信号，以增加胰岛素分泌。IL-33-ILC2轴在急性β细胞应激后被激活，但在慢性肥胖症中却存在缺陷。因此，IL-33注射可以挽救肥胖小鼠的胰岛功能。我们的发现提供了证据，即胰岛来源的IL-33，ILC2s和髓样细胞之间的免疫代谢串扰会促进胰岛素分泌。