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Neutrophil extracellular traps promote macrophage inflammation and impair atherosclerosis resolution in diabetic mice
Tatjana Josefs, … , Jaume Amengual, Edward A. Fisher
Tatjana Josefs, … , Jaume Amengual, Edward A. Fisher
Published March 19, 2020
Citation Information: JCI Insight. 2020;5(7):e134796. https://doi.org/10.1172/jci.insight.134796.
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Research Article Cardiology Inflammation

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

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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 1

Neutrophil extracellular traps in atherosclerotic plaques skew macrophages to a proinflammatory phenotype.

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Neutrophil extracellular traps in atherosclerotic plaques skew macrophag...
(A) Representative atherosclerotic plaque section stained for neutrophil extracellular traps (NETs), as determined by colocalization of myeloperoxidase (MPO), the lymphocyte antigen 6 complex locus G6D (Ly6G), citrullinated histone H3 (H3Cit), and macrophages (CD68). CD68+ cells were collected via laser capture microdissection (LCM) in NET+ and NET– areas and sequenced. Scale bar: 100 μm. (B) Heatmap and (C) volcano plot showing differential gene expression in NET+ versus NET– macrophages. (D) Upregulation of the glycolysis and (E) inflammasome pathways in NET+ compared with NET– macrophages, as determined using Ingenuity Pathway Analysis. (F) Immunofluorescence staining and (G) quantification confirming the inflammasome pathway activation (nod-like receptor family pyrin domain-containing 3 [NLRP3]) in NETs+ area. Scale bar: 50 μm. (H) Quantification of iNOS immunofluorescence staining showing an increase in iNOS in NET+ versus NET– areas (%DAPI). n = 3–5/group, *P < 0.05 using unpaired t test.

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