STING signaling in islet macrophages impairs insulin secretion in obesity

The innate immune regulator stimulator of interferon genes (STING) mediates self-DNA sensing and leads to the induction of type I interferons and inflammatory cytokines, which promotes the progression of various inflammatory and autoimmune diseases. Innate immune system plays a critical role in regulating obesity-induced islet dysfunction, whereas the potential effect of STING signaling is not fully understood. Here, we demonstrate that STING is mainly expressed and activated in islet macrophages upon high-fat diet (HFD) feeding. Sting(-/-) alleviates HFD-induced islet inflammation by inhibiting the expression of pro-inflammatory cytokines and the infiltration of macrophages. Mechanically, palmitic acid incubation promotes mitochondrial DNA leakage into the cytosol and subsequently activates STING pathway in macrophages. Additionally, STING activation in macrophages impairs glucose-stimulated insulin secretion by mediating the engulfment of beta cell insulin secretory granules. Pharmacologically inhibiting STING activation enhances insulin secretion to control hyperglycemia. Together, our results reveal a regulatory mechanism in controlling the islet inflammation and insulin secretion in diet-induced obesity and suggest that selective blocking of the STING activation may be a promising strategy for treating type 2 diabetes.