Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Xinmin, Changchun, Jilin Province 130021, China.
Curr Neuropharmacol. 2023;21(3):621-650. doi: 10.2174/1570159X20666220706115957.
As the first peripheral immune cells to enter the brain after ischemic stroke, neutrophils are important participants in stroke-related neuroinflammation. Neutrophils are quickly mobilized from the periphery in response to a stroke episode and cross the blood-brain barrier to reach the ischemic brain parenchyma. This process involves the mobilization and activation of neutrophils from peripheral immune organs (including the bone marrow and spleen), their chemotaxis in the peripheral blood, and their infiltration into the brain parenchyma (including disruption of the blood-brain barrier, inflammatory effects on brain tissue, and interactions with other immune cell types). In the past, it was believed that neutrophils aggravated brain injuries through the massive release of proteases, reactive oxygen species, pro-inflammatory factors, and extracellular structures known as neutrophil extracellular traps (NETs). With the failure of early clinical trials targeting neutrophils and uncovering their underlying heterogeneity, our view of their role in ischemic stroke has become more complex and multifaceted. As neutrophils can be divided into N1 and N2 phenotypes in tumors, neutrophils have also been found to have similar phenotypes after ischemic stroke, and play different roles in the development and prognosis of ischemic stroke. N1 neutrophils are dominant during the acute phase of stroke (within three days) and are responsible for the damage to neural structures via the aforementioned mechanisms. However, the proportion of N2 neutrophils gradually increases in later phases, and this has a beneficial effect through the release of anti-inflammatory factors and other neuroprotective mediators. Moreover, the N1 and N2 phenotypes are highly plastic and can be transformed into each other under certain conditions. The pronounced differences in their function and their high degree of plasticity make these neutrophil subpopulations promising targets for the treatment of ischemic stroke.
作为缺血性中风后第一个进入大脑的外周免疫细胞，中性粒细胞是与中风相关的神经炎症的重要参与者。中性粒细胞会迅速从外周动员起来，以应对中风发作，并穿过血脑屏障到达缺血性脑实质。这个过程涉及到外周免疫器官（包括骨髓和脾脏）中中性粒细胞的动员和激活，它们在外周血液中的趋化作用，以及它们对脑实质的浸润（包括血脑屏障的破坏、对脑组织的炎症作用以及与其他免疫细胞类型的相互作用）。过去，人们认为中性粒细胞通过大量释放蛋白酶、活性氧、促炎因子和称为中性粒细胞胞外诱捕网（NETs）的细胞外结构来加重脑损伤。随着针对中性粒细胞的早期临床试验失败和对其潜在异质性的揭示，我们对其在缺血性中风中的作用的看法变得更加复杂和多方面。由于中性粒细胞在肿瘤中可以分为 N1 和 N2 表型，因此在缺血性中风后也发现中性粒细胞具有类似的表型，并在缺血性中风的发展和预后中发挥不同的作用。N1 中性粒细胞在中风的急性期（3 天内）占主导地位，通过上述机制对神经结构造成损伤。然而，N2 中性粒细胞的比例在后期逐渐增加，并通过释放抗炎因子和其他神经保护介质产生有益的效果。此外，N1 和 N2 表型具有高度的可塑性，可以在某些条件下相互转化。这些中性粒细胞亚群在功能上存在显著差异，并且具有高度的可塑性，使它们成为治疗缺血性中风的有前途的靶点。
