Editors' ChoiceAtherosclerosis

A charged NET accelerates atherosclerosis in acute infections

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Science Translational Medicine  02 Dec 2020:
Vol. 12, Issue 572, eabf7526
DOI: 10.1126/scitranslmed.abf7526


Neutrophil extracellular traps (NETs) accelerate vascular inflammation in a model of endotoxinemia.

The first evidence of an association between atherosclerosis and acute infection was made by Gilbert and Lion in 1889, when they observed atherosclerotic changes to the aortas of rabbits after infection with Salmonella Typhi, Gram-negative bacteria expressing lipopolysaccharide (LPS). After many years of intense investigations and growing evidence of increased risk of cardiovascular events within 7 days of acute infection, the mechanisms underlying such associations remain largely elusive.

Schumski et al. performed a series of elegant studies to reveal that LPS enhances vascular inflammation and atherosclerotic lesion size in Apoe−/− and Apoe−/− Cx3cr1GFP reporter mice expressing enhanced green fluorescent protein (EGFP) in monocytes. Specifically, the authors showed that neutrophil extracellular traps (NETs), released from activated neutrophils upon LPS peritoneal injection, facilitated monocyte accumulation into the atherosclerotic arterial wall. This effect was accompanied by an acute depletion of circulating monocytes and neutrophils and by increased plasma double-stranded DNA (dsDNA). Interestingly, plasma dsDNA, a surrogate marker of NETs, was higher in patients hospitalized with Gram-negative rod bacteremia or sepsis than in patients without infection, confirming the clinical relevance of these experimental evidence.

Mechanistically, vascular inflammation and heightened atherosclerosis were completely prevented by the specific inhibition of NET formation using BB Cl-amidine, a peptidylarginine deiminase inhibitor that disrupts NETs. Classical monocyte adhesion to the NET luminal scaffold was prevented by NET degradation with deoxyribonuclease I (DNase I). Further, the authors found that the adhesion of monocytes to luminal NETs was dependent on electrostatic interactions between negatively charged monocytes and the cationic protein histone H2a present on NETs. Neutralization of histone H2a, using a potent cyclical histone 2a interference peptide (CHIP), reduced adhesion of monocytes to NETs and diminished arterial adhesion of neutrophils and monocytes in vivo, leading to reduced lesion sizes.

Schumski et al. reveal a key immune mechanism that could contribute to the increased risk for cardiovascular events during acute infection. The pharmacological inhibition of histone H2a is a promising strategy to prevent cardiovascular outcomes in the acute phases of an infection.

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