Neutrophils as regulators of cardiovascular inflammation

Neutrophils have traditionally been viewed as bystanders or biomarkers of cardiovascular disease. However, studies in the past decade have demonstrated the important functions of neutrophils during cardiovascular inflammation and repair. In this Review, we discuss the influence of traditional and novel cardiovascular risk factors on neutrophil production and function. We then appraise the current knowledge of the contribution of neutrophils to the different stages of atherosclerosis, including atherogenesis, plaque destabilization and plaque erosion. In the context of cardiovascular complications of atherosclerosis, we highlight the dichotomous role of neutrophils in pathogenic and repair processes in stroke, heart failure, myocardial infarction and neointima formation. Finally, we emphasize how detailed knowledge of neutrophil functions in cardiovascular homeostasis and disease can be used to generate therapeutic strategies to target neutrophil numbers, functional status and effector mechanisms. In this Review, Soehnlein and colleagues discuss the role of neutrophils in cardiovascular inflammation and repair, describing the effect of cardiovascular risk factors on neutrophil production and function, appraising the contribution of neutrophils to the different stages of atherosclerosis and its clinical manifestations, and highlighting the evolving therapeutic strategies for targeting neutrophil numbers, functional status and effector mechanisms. Key points Hypercholesterolaemia and hyperglycaemia heighten neutrophil production in the bone marrow and at extramedullary sites, thereby accelerating cardiovascular inflammation. Lifestyle factors, including stress, disturbed sleep and nutrition, influence cardiovascular inflammation in part by altering neutrophil production in the bone marrow. Neutrophils accelerate all stages of atherosclerosis by fostering monocyte recruitment and macrophage activation and through cytotoxicity. During complications of cardiovascular inflammation, such as neointima formation and myocardial infarction, neutrophils have reparative functions primarily by promoting endothelial regrowth and angiogenesis. In cardiac hypertrophy and stroke, neutrophil-driven macrophage activation and stimulation of coagulation have a negative effect. Time-specific and site-specific interference with neutrophil recruitment to large arteries and inhibition of neutrophil extracellular trap discharge or neutralization of active components of neutrophil ext