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

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

doi:10.1172/jci.insight.134796

Cited by 147 publications

(103 citation statements)

References 43 publications

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“…Interestingly, we observed that BMDMs incubated with NET-DNA did not show changes in the expression levels of DNase1 or DNase1L3 mRNA (Supplementary Figure 4A) indicating a lack of transcriptional regulation in this process. Consistent with this observation, our analysis of publicly available data 20 revealed no significant differences in the mRNA expression levels of DNase1 and DNase1L3 in plaque macrophages that are in the proximity of NET-DNA+ area vs.…”

Section: Dnase1 and Dnase1l3supporting

confidence: 83%

“…Previous studies have shown that accumulation of extracellular DNA, particularly NETotic, necrotic, and necroptotic DNA is involved in atherosclerotic plaque progression [6][7][8] . Most importantly, treatment with DNase1 has been demonstrated to prevent plaque progression in early atherosclerosis 9,19 and promote plaque regression in diabetic mice 20 . Based on these previous studies as well as our data demonstrating impaired DNase response during hypercholesterolemia (Figure 2E), we next addressed the specific question whether restoration of DNase activity via exogenous supplementation of DNase1 could decrease plaque inflammation and prevent plaque progression specifically in the context of advanced atherosclerosis which has not been explored so far.…”

Section: Dnase1 Treatment Decreases Atherosclerotic Plaque Extracellumentioning

confidence: 99%

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Hypercholesterolemia Impairs Clearance of Extracellular DNA and Promotes Inflammation and Atherosclerotic Plaque Progression

Dhawan

Bhattacharya

Narayanan

et al. 2020

Preprint

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Defects in clearance of extracellular DNA due to sub-optimal activity of DNase results in exacerbated inflammation and contributes to the pathophysiology of atherosclerosis and other inflammatory diseases. However, the physiological mechanisms that regulate systemic DNase levels and the basis of its functional impairment during disease are poorly understood. Using a mouse model of experimental increase in systemic extracellular DNA levels, we identify the existence of a physiologic DNA-induced DNase response. Importantly, hypercholesterolemia in mice impairs this critical DNA-induced DNase response through an endoplasmic reticulum stress-mediated mechanism with consequences in advanced atherosclerotic plaque progression including increased extracellular DNA accumulation, exacerbated inflammation, and development of pathological features of necrotic rupture-prone vulnerable plaques. From a translational standpoint in humans, we demonstrate that individuals with hypercholesterolemia have elevated systemic extracellular DNA levels and decreased plasma DNase activity. These data suggest that the restoration of DNA-induced DNase response could be a potential therapeutic strategy to promote inflammation resolution during hypercholesterolemia.

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Section: Dnase1 and Dnase1l3supporting

confidence: 83%

Section: Dnase1 Treatment Decreases Atherosclerotic Plaque Extracellumentioning

confidence: 99%

Hypercholesterolemia Impairs Clearance of Extracellular DNA and Promotes Inflammation and Atherosclerotic Plaque Progression

Dhawan

Bhattacharya

Narayanan

et al. 2020

Preprint

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“…NETs are extracellular webs of DNA, histones, and microbicidal proteins that appear to perpetuate many types of lung disease including smoking-related disease (41), cystic fibrosis (42), and ARDS (14,43,44). NETs leverage calprotectin as an antimicrobial strategy against Candida (45) and Aspergillus (46), but, when left unchecked, NETs are also an important source of macrophage activation (47,48) and microvascular occlusion (49,50). This is another topic that in our opinion requires further and urgent investigation.…”

Section: Discussionmentioning

confidence: 96%

Neutrophil calprotectin identifies severe pulmonary disease in COVID-19

Shi

Zuo

Yalavarthi

et al. 2020

Preprint

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Severe cases of coronavirus disease 2019 (COVID-19) are regularly complicated by respiratory failure. While it has been suggested that elevated levels of blood neutrophils associate with worsening oxygenation in COVID-19, it is unknown whether neutrophils are drivers of the thrombo-inflammatory storm or simple bystanders. To better understand the potential role of neutrophils in COVID-19, we measured levels of the neutrophil activation marker S100A8/A9 (calprotectin) in hospitalized patients and determined its relationship to severity of illness and respiratory status. Patients with COVID-19 (n=172) had markedly elevated levels of calprotectin in their blood. Calprotectin tracked with other acute phase reactants including C-reactive protein, ferritin, lactate dehydrogenase, and absolute neutrophil count, but was superior in identifying patients requiring mechanical ventilation. In longitudinal samples, calprotectin rose as oxygenation worsened. When tested on day 1 or 2 of hospitalization (n=94 patients), calprotectin levels were significantly higher in patients who progressed to severe COVID-19 requiring mechanical ventilation (8039 +/- 7031 ng/ml, n=32) as compared to those who remained free of intubation (3365 +/- 3146, p<0.0001). In summary, serum calprotectin levels track closely with current and future COVID-19 severity, implicating neutrophils as potential perpetuators of inflammation and respiratory compromise in COVID-19.

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“…Cholesterol crystal images were acquired using an Axioscan microscope (Carl Zeiss, Jena, Germany) using a 10x air objective. Cholesterol crystal images were captured using polarized light and represented as the percentage of plaque area, as previously described (22). Nuclear staining with 4′,6-diamidino-2-phenylindole (DAPI, Sigma) was used as a counterstain.…”

Section: Aortic Root Analysismentioning

confidence: 99%

β-Carotene conversion to vitamin A delays atherosclerosis progression by decreasing hepatic lipid secretion in mice

Zhou

Pinos

et al. 2020

Journal of Lipid Research

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Atherosclerosis is characterized by the pathological accumulation of cholesterol-laden macrophages in the arterial wall. Atherosclerosis is also the main underlying cause of cardiovascular diseases (CVDs), and its development is largely driven by elevated plasma cholesterol. Strong epidemiological data find an inverse association between plasma β-carotene with atherosclerosis, and we recently showed that β-carotene oxygenase 1 (BCO1) activity, responsible for β-carotene cleavage to vitamin A, is associated with reduced plasma cholesterol in humans and mice. In this study, we explore whether intact β-carotene or vitamin A affect atherosclerosis progression in the atheroprone low-density lipoprotein receptor (LDLR) - deficient mice. In comparison to control-fed Ldlr-/- mice, β-carotene-supplemented mice showed reduced atherosclerotic lesion size at the level of the aortic root and reduced plasma cholesterol levels. These changes were absent in Ldlr-/-/Bco1-/- mice, despite accumulating β-carotene in plasma and atherosclerotic lesions. We discarded the implication of myeloid BCO1 in the development of atherosclerosis by performing bone marrow transplant experiments. Lipid production assays found that retinoic acid, the active form of vitamin A, reduced the secretion of newly synthetized triglyceride and cholesteryl ester in cell culture and mice. Overall, our findings provide insights into the role of BCO1 activity and vitamin A in atherosclerosis progression through the regulation of hepatic lipid metabolism.

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

Cited by 147 publications

References 43 publications

Hypercholesterolemia Impairs Clearance of Extracellular DNA and Promotes Inflammation and Atherosclerotic Plaque Progression

Hypercholesterolemia Impairs Clearance of Extracellular DNA and Promotes Inflammation and Atherosclerotic Plaque Progression

Neutrophil calprotectin identifies severe pulmonary disease in COVID-19

β-Carotene conversion to vitamin A delays atherosclerosis progression by decreasing hepatic lipid secretion in mice

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