Neutrophil Extracellular Traps (NETs) as drivers of atherosclerosis: Pathogenic mechanisms and therapeutic opportunities

Cardiovascular diseases (CVDs) are the leading cause of death globally. The primary pathological process underlying CVDs is atherosclerosis, a chronic lipid-driven inflammatory condition that results in the narrowing of medium- and large-arteries due to a build-up of fibrofatty, leukocyte-rich plaques. Adverse clinical outcomes are usually a result of plaque erosion or rupture which result in acute luminal thrombosis with ensuing tissue ischaemia. Immune cell infiltration and the associated inflammation are recognized as key drivers of the development of unstable plaques. Whilst the role of macrophages, dendritic cells, T- and B-lymphocytes are extensively documented in the progression of atherosclerosis, the role of neutrophils, which are the dominant leukocyte subset in humans, is relatively understudied. Interestingly, studies in the last decade have shed light on the critical role of neutrophil extracellular traps (NETs) in mediating inflammasome activation, plaque progression, and adverse clinical outcomes. NETs are complex extracellular DNA structures released by neutrophils undergoing death by a specialized process of NETosis. This review will comprehensively examine the key drivers of NETosis in atherosclerosis, mechanisms of NET clearance, the pathogenic role of NETs in plaque progression, and finally novel pharmacological approaches to target NETs to prevent atherothrombosis and its associated clinical complications.