STING signaling in infiltrating macrophages mediates islet function 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 remains unclear. Here, we demonstrate that STING is mainly expressed and activated in islet macrophages upon high-fat diet (HFD) feeding. Knocking-out STING alleviates HFD-induced islet inflammation by inhibiting the expression of pro-inflammatory cytokines and infiltration of macrophages. Mechanically, palmitic acid incubation promotes mitochondrial DNA leakage into the cytosol and subsequently activates cyclic AMP-GMP synthase (cGAS)-STING pathway in macrophages. Additionally, STING activation in macrophages impairs glucose-stimulated insulin secretion by mediating the engulfment of β cell insulin secretory granules. Genetically or pharmacologically inhibiting STING activation boosts insulin secretion and hyperglycemia. Together, these findings 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 maybe a promising strategy for treating type 2 diabetes.