Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, New York, USA.
Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, Illinois, USA.
JCI Insight. 2020 Apr 9;5(7):134796. doi: 10.1172/jci.insight.134796.
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.
中性粒细胞胞外诱捕网（NETs）促进炎症和动脉粥样硬化进展。糖尿病患者 NETs 增加，并损害伤口愈合过程中的炎症消退。类似于伤口愈合的动脉粥样硬化消退在糖尿病中也受到损害。因此，我们假设 NETs 通过增加斑块炎症来阻碍糖尿病中的动脉粥样硬化消退。事实上，对低密度脂蛋白受体缺陷（Ldlr-/-）小鼠中 NET+和 NET-区域斑块巨噬细胞的转录组分析显示，炎症小体和糖酵解途径上调，表明炎症表型增强。我们发现，NETs 在动脉粥样硬化消退过程中减少，这是通过降低非糖尿病小鼠的高脂血症诱导的，但它们在糖尿病中持续存在，加剧了巨噬细胞炎症并损害了消退。在糖尿病小鼠中，脱氧核糖核酸酶 1 治疗减少了斑块 NET 含量和巨噬细胞炎症，促进了降脂后的动脉粥样硬化消退。鉴于降脂后患有糖尿病的人类也表现出动脉粥样硬化消退受损，这些数据表明 NETs 导致该人群心血管疾病风险增加，是一个潜在的治疗靶点。
