Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.
School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.
Curr Neuropharmacol. 2023;21(10):2079-2096. doi: 10.2174/1570159X21666230308090351.
Cerebral ischemic injury, one of the leading causes of morbidity and mortality worldwide, triggers various central nervous system (CNS) diseases, including acute ischemic stroke (AIS) and chronic ischemia-induced Alzheimer's disease (AD). Currently, targeted therapies are urgently needed to address neurological disorders caused by cerebral ischemia/reperfusion injury (CI/RI), and the emergence of neutrophil extracellular traps (NETs) may be able to relieve the pressure. Neutrophils are precursors to brain injury following ischemic stroke and exert complicated functions. NETs extracellularly release reticular complexes of neutrophils, i.e., double-stranded DNA (dsDNA), histones, and granulins. Paradoxically, NETs play a dual role, friend and foe, under different conditions, for example, physiological circumstances, infection, neurodegeneration, and ischemia/reperfusion. Increasing evidence indicates that NETs exert anti-inflammatory effects by degrading cytokines and chemokines through protease at a relatively stable and moderate level under physiological conditions, while excessive amounts of NETs release (NETosis) irritated by CI/RI exacerbate the inflammatory response and aggravate thrombosis, disrupt the blood-brain barrier (BBB), and initiates sequential neuron injury and tissue damage. This review provides a comprehensive overview of the machinery of NETs formation and the role of an abnormal cascade of NETs in CI/RI, as well as other ischemia-induced neurological diseases. Herein, we highlight the potential of NETs as a therapeutic target against ischemic stroke that may inspire translational research and innovative clinical approaches.
脑缺血损伤是全球发病率和死亡率的主要原因之一，可引发多种中枢神经系统 (CNS) 疾病，包括急性缺血性中风 (AIS) 和慢性缺血诱导的阿尔茨海默病 (AD)。目前，迫切需要针对脑缺血/再灌注损伤 (CI/RI) 引起的神经障碍的靶向治疗方法，而中性粒细胞胞外诱捕网 (NETs) 的出现可能能够缓解这种压力。中性粒细胞是缺血性中风后脑损伤的前体，具有复杂的功能。NETs 会从体外释放出中性粒细胞的网状复合物，即双链 DNA (dsDNA)、组蛋白和颗粒酶。NETs 在不同的条件下表现出双重作用，即朋友和敌人，这是矛盾的，例如在生理情况下、感染、神经退行性变和缺血/再灌注时。越来越多的证据表明，NETs 通过在相对稳定和适度的水平上通过蛋白酶降解细胞因子和趋化因子发挥抗炎作用，而由 CI/RI 刺激的过量 NETs 释放（NETosis）会加剧炎症反应并加重血栓形成、破坏血脑屏障 (BBB)，并引发连续的神经元损伤和组织损伤。本综述全面概述了 NETs 的形成机制以及异常 NETs 级联在 CI/RI 中的作用，以及其他缺血性诱导的神经疾病。在这里，我们强调了 NETs 作为治疗缺血性中风的潜在靶点的可能性，这可能会激发转化研究和创新的临床方法。
