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 inflamma...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 ofβcell 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 dietinduced obesity and suggest that selective blocking of the STING activation may be a promising strategy for treating type 2 diabetes.展开更多
Sterile inflammation characterized by unresolved chronic inflammation is well established to promote the progression of multiple autoimmune diseases,metabolic disorders,neurodegenerative diseases,and cardiovascular di...Sterile inflammation characterized by unresolved chronic inflammation is well established to promote the progression of multiple autoimmune diseases,metabolic disorders,neurodegenerative diseases,and cardiovascular diseases,collectively termed‘sterile inflammatory diseases’.By recognizing host-derived DNA,cyclic guanosine monophosphate–adenosine monophosphate synthase(cGAS)activates endoplasmic reticulum-associated stimulator of interferon genes(STING),which leads to the induction of type I interferons and inflammatory cytokines or immunogenic cell death that promotes sterile inflammation.Additionally,the DNA/cGAS-independent mode of STING activation has also been characterized in the progression of several sterile inflammatory diseases.This review focuses on the molecular mechanism of cGAS-dependent and cGAS-independent STING signaling under various disease conditions,particularly highlighting the diverse initiators upon this signaling pathway.We also summarize recent advances in the discovery of antagonists targeting cGAS and STING and the evaluation of their efficiencies in preclinical models.Finally,we discuss potential differences in the clinical applications of the specific antagonists,which may shed light on the precision therapeutic interventions.展开更多
基金supported by the National Key Research and Development Program of China(2022YFC2303200,2021YFF0702003)China Postdoctoral Research Program(2019TQ0356)+3 种基金the“Double First-Class”Project of China Pharmaceutical University(CPU2022QZ01)the National Natural Science Foundation of China(31730018,82171751,82204408)the Natural Science Foundation of Chongqing(CSTB2022NSCQ-MSX1114)Key R&D Project of Jiangsu Province(BE2020725)。
文摘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 ofβcell 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 dietinduced obesity and suggest that selective blocking of the STING activation may be a promising strategy for treating type 2 diabetes.
基金funded by the National Natural Science Foundation of China(31730018,81672029,3173000227,and 31470428)National Key R&D Program of China(2016YFA0501800)China Postdoctoral Research Program(2019TQ0356 to Z.H.).
文摘Sterile inflammation characterized by unresolved chronic inflammation is well established to promote the progression of multiple autoimmune diseases,metabolic disorders,neurodegenerative diseases,and cardiovascular diseases,collectively termed‘sterile inflammatory diseases’.By recognizing host-derived DNA,cyclic guanosine monophosphate–adenosine monophosphate synthase(cGAS)activates endoplasmic reticulum-associated stimulator of interferon genes(STING),which leads to the induction of type I interferons and inflammatory cytokines or immunogenic cell death that promotes sterile inflammation.Additionally,the DNA/cGAS-independent mode of STING activation has also been characterized in the progression of several sterile inflammatory diseases.This review focuses on the molecular mechanism of cGAS-dependent and cGAS-independent STING signaling under various disease conditions,particularly highlighting the diverse initiators upon this signaling pathway.We also summarize recent advances in the discovery of antagonists targeting cGAS and STING and the evaluation of their efficiencies in preclinical models.Finally,we discuss potential differences in the clinical applications of the specific antagonists,which may shed light on the precision therapeutic interventions.