Shetty Shravya, Subramanian Manikandan
Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.
Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK; William Harvey Research Institute, Queen Mary University of London, UK.
Pharmacol Ther. 2025 Oct;274:108917. doi: 10.1016/j.pharmthera.2025.108917. Epub 2025 Aug 20.
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.
心血管疾病（CVDs）是全球主要的死亡原因。CVDs的主要病理过程是动脉粥样硬化，这是一种由脂质驱动的慢性炎症状态，由于富含纤维脂肪、白细胞的斑块积聚，导致中大型动脉狭窄。不良临床结局通常是斑块侵蚀或破裂的结果，这会导致急性管腔血栓形成并随之出现组织缺血。免疫细胞浸润和相关炎症被认为是不稳定斑块发展的关键驱动因素。虽然巨噬细胞、树突状细胞、T淋巴细胞和B淋巴细胞在动脉粥样硬化进展中的作用已有大量文献记载，但作为人类主要白细胞亚群的中性粒细胞的作用相对研究较少。有趣的是，过去十年的研究揭示了中性粒细胞胞外陷阱（NETs）在介导炎性小体激活、斑块进展和不良临床结局中的关键作用。NETs是中性粒细胞通过一种特殊的NETosis过程死亡时释放的复杂细胞外DNA结构。本综述将全面探讨动脉粥样硬化中NETosis的关键驱动因素、NET清除机制、NETs在斑块进展中的致病作用，以及最后针对NETs的新型药理学方法，以预防动脉粥样硬化血栓形成及其相关临床并发症。
