Abstract 13405: Genetic Deletion of Stimulator of Interferon Genes Attenuates Atherogenesis in Apolipoprotein E-deficient Mice

Abstract

Introduction: Recent studies show the contribution of innate immunity system to the pathogenesis of inflammatory diseases, including atherosclerosis. Stimulation of interferon genes (STING), originally known as a cytosolic DNA sensor, recognizes cytosolic DNA fragments, activating innate immunity. Here, we investigated whether STING contributes to the development of vascular inflammation and atherogenesis in apolipoprotein E-deficient (Apoe –/– ) mice. Methods and Results: The expression of STING increased in the atherosclerotic aorta in both gene and protein expression levels. STING-deficient Apoe –/– (STING –/– Apoe –/– ) mice reduced atherosclerotic lesions in the aortic arch ( P <0.05), along with the reduction of lipid and macrophage accumulation in atherosclerotic plaques ( P <0.05, respectively), and inflammatory molecule expression in the aorta compared with those in Apoe –/– mice after 20 weeks on a western-type diet. Also, pharmacologic blockade of STING in Apoe –/– mice for 12 weeks treatment attenuated atherogenesis in the aortic arch ( P <0.05), reduced the accumulation of lipid in atherosclerotic plaques ( P <0.05) with no alteration of metabolic parameters. Restoration of STING in bone marrow in STING –/– Apoe –/– mice promoted atherogenesis ( P <0.05), lipid deposition ( P <0.05), and vascular inflammation. cGAMP, a specific STING agonist, or mitochondrial DNA extracted from macrophages promoted expression of inflammatory molecules more effectively in Apoe -/- macrophages than in STING –/– Apoe –/– macrophages, while C-176, a specific STING inhibitor, attenuated these inflammatory responses. The results of western blotting showed the involvement of NF-κB and IRF-3 signaling in STING-associated vascular inflammation and macrophage activation. Furthermore, in humans, STING expression was confirmed in atherosclerotic lesions in the carotid artery. Conclusion: STING signaling activates macrophages, promotes vascular inflammation and atherosclerosis in Apoe -/- mice. Our results suggest that STING may serve as a potential therapeutic target for atherosclerosis.