The perpetuation of inflammation is an important pathophysiological contributor to the global medical burden. Chronic inflammation is promoted by non-programmed cell death1,2; however, how inflammation is instigated, its cellular and molecular mediators, and its therapeutic value are poorly defined. Here we use mouse models of atherosclerosis—a major underlying cause of mortality worldwide—to demonstrate that extracellular histone H4-mediated membrane lysis of smooth muscle cells (SMCs) triggers arterial tissue damage and inflammation. We show that activated lesional SMCs attract neutrophils, triggering the ejection of neutrophil extracellular traps that contain nuclear proteins. Among them, histone H4 binds to and lyses SMCs, leading to the destabilization of plaques; conversely, the neutralization of histone H4 prevents cell death of SMCs and stabilizes atherosclerotic lesions. Our data identify a form of cell death found at the core of chronic vascular disease that is instigated by leukocytes and can be targeted therapeutically.
Neutrophil extracellular traps (NETs) are networks of extracellular genetic material decorated with proteins of nuclear, granular and cytosolic origin that activated neutrophils expel under pathogenic inflammatory conditions. NETs are part of the host’s innate immune defense system against invading pathogens. Interestingly, these extracellular structures can also be released in response to sterile inflammatory stimuli (e.g., shear stress, lipidic molecules, pro-thrombotic factors, aggregated platelets, or pro-inflammatory cytokines), as in atherosclerosis disease. Indeed, NETs have been identified in the intimal surface of diseased arteries under cardiovascular disease conditions, where they sustain inflammation via NET-mediated cell-adhesion mechanisms and promote cellular dysfunction and tissue damage via NET-associated cytotoxicity. This review will focus on (1) the active role of neutrophils and NETs as underestimated players of the inflammatory process during atherogenesis and lesion progression; (2) how these extracellular structures communicate with the main cell types present in the atherosclerotic lesion in the arterial wall; and (3) how these neutrophil effector functions interplay with lifestyle-derived risk factors such as an unbalanced diet, physical inactivity, smoking or lack of sleep quality, which represent major elements in the development of cardiovascular disease.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.