Neutrophil extracellular traps promote macrophage inflammation and impair atherosclerosis resolution in diabetic mice
Tatjana Josefs, Tessa J. Barrett, Emily J. Brown, Alexandra Quezada, Xiaoyun Wu, Maud Voisin, Jaume Amengual, Edward A. Fisher
Tatjana Josefs, Tessa J. Barrett, Emily J. Brown, Alexandra Quezada, Xiaoyun Wu, Maud Voisin, Jaume Amengual, Edward A. Fisher
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Research Article Cardiology Inflammation

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

Abstract

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.

Authors

Tatjana Josefs, Tessa J. Barrett, Emily J. Brown, Alexandra Quezada, Xiaoyun Wu, Maud Voisin, Jaume Amengual, Edward A. Fisher

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Figure 2

DNase1 treatment promotes atherosclerosis resolution in diabetic mice.

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DNase1 treatment promotes atherosclerosis resolution in diabetic mice. (...
(A) Male Ldlr–/– mice were fed a Western diet for 16 weeks to develop baseline plaques. At week 15, a subset of mice received streptozocin injections to induce diabetes. At week 16, a subset of mice were harvested for baseline measures, and all other mice were switched to a chow diet to induce resolution of plaques. These mice were then split into 2 groups and over a 4-week period received either DNase1 (62.5 μg/mouse) or vehicle injections every other day. At week 20, mouse tissues were harvested for plaque analyses. (B) NET staining and (C) quantification in aortic roots, as determined by composite staining of myeloperoxidase (MPO), the lymphocyte antigen 6 complex locus G6D (Ly6G), and citrullinated histone H3 (H3Cit). Scale bar: 100 μm. (D) Representative images and (E) quantification of CD68 staining as a marker of plaque macrophage content. Scale bar: 100 μm. Data are shown as mean ± SEM. n = 7–12/group, *P < 0.05, 1-way ANOVA with Tukey’s multiple comparison test.