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Neutrophil extracellular traps contributing to atherosclerosis: From pathophysiology to clinical implications.

ABSTRACT: Neutrophil extracellular traps (NETs) are network-like structures of chromatin filaments decorated by histones, granules, and cytoplasmic-derived proteins expelled by activated neutrophils under multiple pathogenic conditions. NETs not only capture pathogens in innate immunity but also respond to sterile inflammatory stimuli in atherosclerosis, such as lipoproteins and inflammatory cytokines. Atherosclerosis is a lipid-driven chronic inflammatory disease characterized by the accumulation and transformation of inflammatory cells, and smooth muscle cells in the intimal space. NETs-derived extracellular components possess toxic and proinflammatory properties leading to cellular dysfunction and tissue damage, which may establish a link among lipid metabolism, inflammatory immunity, and atherosclerosis. In this review, we discuss recent advances regarding the role of NETs engaged in the pathogenesis of atherosclerosis, particularly focusing on the interaction with lipids and inflammasomes, crosstalk with smooth muscle cells and inflammatory cells, and the association with aging. We also evaluate the current knowledge on the potential of NETs as biomarkers and therapeutic targets for atherosclerosis and its related diseases in clinical practice.

SUBMITTER: Gu C

PROVIDER: S-EPMC10625340 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Neutrophil extracellular traps contributing to atherosclerosis: From pathophysiology to clinical implications.

Gu Chun C Pang Bo B Sun Shipeng S An Cheng C Wu Min M Wang Na N Yuan Yuliang Y Liu Guijian G

Experimental biology and medicine (Maywood, N.J.) 20230715 15

Neutrophil extracellular traps (NETs) are network-like structures of chromatin filaments decorated by histones, granules, and cytoplasmic-derived proteins expelled by activated neutrophils under multiple pathogenic conditions. NETs not only capture pathogens in innate immunity but also respond to sterile inflammatory stimuli in atherosclerosis, such as lipoproteins and inflammatory cytokines. Atherosclerosis is a lipid-driven chronic inflammatory disease characterized by the accumulation and tra ...[more]

PMID: 37452714

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Project description:RationaleMitochondrial oxidative stress (mitoOS) has been shown to be increased in various cell types in human atherosclerosis and with aging. However, the role of cell type-specific mitoOS in atherosclerosis in the setting of advanced age and the molecular mechanisms remains to be determined in vivo.ObjectiveThe aim of this study was to examine the role of myeloid cell mitoOS in atherosclerosis in aged mice.Approach and resultsLethally irradiated low-density lipoprotein receptor-deficient mice (Ldlr-/-) were reconstituted with bone marrow from either wild-type or mitochondrial catalase (mCAT) mice. mCAT transgenic mice contain ectopically expressed human catalase gene in mitochondria, which reduces mitoOS. Starting at the age of 36 weeks, mice were fed the Western-type diet for 16 weeks. We found that mitoOS in lesional myeloid cells was suppressed in aged mCAT→Ldlr-/- chimeric mice compared with aged controls, and this led to a significant reduction in aortic root atherosclerotic lesion area despite higher plasma cholesterol levels. Neutrophil extracellular traps (NETs), a proinflammatory extracellular structure that contributes to atherosclerosis progression, were significantly increased in the lesions of aged mice compared with lesions of younger mice. Aged mCAT→Ldlr-/- mice had less lesional neutrophils and decreased NETs compared with age-matched wild-type→Ldlr-/- mice, whereas young mCAT→ and wild-type→Ldlr-/- mice had comparable numbers of neutrophils and similar low levels of lesional NETs. Using cultured neutrophils, we showed that suppression of mitoOS reduced 7-ketocholesterol-induced NET release from neutrophils of aged but not younger mice.ConclusionsMitoOS in lesional myeloid cells enhanced atherosclerosis development in aged mice, and this enhancement was associated with increased lesional NETs. Thus, mitoOS-induced NET formation is a potentially new therapeutic target to prevent atherosclerosis progression during aging.

Project description:Organ dysfunction is a major concern in sepsis pathophysiology and contributes to its high mortality rate. Neutrophil extracellular traps (NETs) have been implicated in endothelial damage and take part in the pathogenesis of organ dysfunction in several conditions. NETs also have an important role in counteracting invading microorganisms during infection. The aim of this study was to evaluate systemic NETs formation, their participation in host bacterial clearance and their contribution to organ dysfunction in sepsis. C57Bl/6 mice were subjected to endotoxic shock or a polymicrobial sepsis model induced by cecal ligation and puncture (CLP). The involvement of cf-DNA/NETs in the physiopathology of sepsis was evaluated through NETs degradation by rhDNase. This treatment was also associated with a broad-spectrum antibiotic treatment (ertapenem) in mice after CLP. CLP or endotoxin administration induced a significant increase in the serum concentrations of NETs. The increase in CLP-induced NETs was sustained over a period of 3 to 24 h after surgery in mice and was not inhibited by the antibiotic treatment. Systemic rhDNase treatment reduced serum NETs and increased the bacterial load in non-antibiotic-treated septic mice. rhDNase plus antibiotics attenuated sepsis-induced organ damage and improved the survival rate. The correlation between the presence of NETs in peripheral blood and organ dysfunction was evaluated in 31 septic patients. Higher cf-DNA concentrations were detected in septic patients in comparison with healthy controls, and levels were correlated with sepsis severity and organ dysfunction. In conclusion, cf-DNA/NETs are formed during sepsis and are associated with sepsis severity. In the experimental setting, the degradation of NETs by rhDNase attenuates organ damage only when combined with antibiotics, confirming that NETs take part in sepsis pathogenesis. Altogether, our results suggest that NETs are important for host bacterial control and are relevant actors in the pathogenesis of sepsis.

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Neutrophil extracellular traps contributing to atherosclerosis: From pathophysiology to clinical implications.

Publications

Neutrophil extracellular traps contributing to atherosclerosis: From pathophysiology to clinical implications.

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