Neutrophil extracellular traps promote macrophage inflammation and impair atherosclerosis resolution in diabetic mice

Neutrophil extracellular traps (NETs) promote inflammation and atherosclerosis progression. NETs are increased in diabetes and impair the resolution of inflammation during wound healing. Atherosclerosis resolution, a process resembling wound healing, is also impaired in diabetes. Thus, we hypothesized that NETs impede atherosclerosis resolution in diabetes by increasing plaque inflammation. Indeed, transcriptomic profiling of plaque macrophages from NET+ and NET^- areas in low-density lipoprotein receptor-deficient (Ldlr^-/-) mice revealed inflammasome and glycolysis pathway upregulation, indicating a heightened inflammatory phenotype. We found that NETs declined during atherosclerosis resolution, which was induced by reducing hyperlipidemia in nondiabetic mice, but they persisted in diabetes, exacerbating macrophage inflammation and impairing resolution. In diabetic mice, deoxyribonuclease 1 treatment reduced plaque NET content and macrophage inflammation, promoting atherosclerosis resolution after lipid lowering. Given that humans with diabetes also exhibit impaired atherosclerosis resolution with lipid lowering, these data suggest that NETs contribute to the increased cardiovascular disease risk in this population and are a potential therapeutic target.