Neutrophil Extracellular Traps may be a Potential Target for Treating Early Brain Injury in Subarachnoid Hemorrhage
Neutrophil Extracellular Traps may be a Potential Target for Treating Early Brain Injury in Subarachnoid Hemorrhage
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中性粒细胞胞外陷阱可能是治疗蛛网膜下腔出血早期脑损伤的潜在靶点。
DOI：
10.1007/s12975-021-00909-1
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发表时间：
2021-04-14
影响因子：
6.9
通讯作者：
Chen, Gao
中科院分区：
文献类型：
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作者：
Zeng, Hanhai;Fu, Xiongjie;Chen, Gao
神经炎症与蛛网膜下腔出血（SAH）患者的不良预后密切相关。本研究旨在探讨中性粒细胞胞外陷阱（NETs）在SAH中的作用，NETs是无菌性炎症的重要调节因子。在这项研究中，NET形成的标志物，量化的瓜氨酸化组蛋白H3（CitH 3）的水平，SAH后显着增加，并与SAH的严重程度。CitH 3在外周血中在12 h达到峰值，在脑中在24 h达到峰值。肽基精氨酸脱亚胺酶4（PAD 4）选择性拮抗剂GSK 484的管理基本上衰减SAH诱导的脑水肿和神经元损伤。此外，NET抑制的益处也通过DNA酶I处理和中性粒细胞耗竭证实。从机制上讲，NET在体外显著加剧了小胶质细胞炎症。NET的形成通过促进小胶质细胞的活化和增加TNF-α、IL-1β和IL-6的水平而加重神经炎症，而抑制NET则通过降低这些促炎因子的水平而表现出抗炎作用。此外，神经源性肺水肿（NPE）是SAH后的一种严重非神经系统并发症，与高水平的NET形成相关。然而，GSK 484有效地抑制NPE小鼠肺中NET的形成，从而防止嗜中性粒细胞浸润的扩散并减轻肺泡上皮的肿胀。总之，NETs促进SAH后的神经炎症，而药物抑制PAD 4-NETs可减轻SAH引起的炎症损伤。这些结果支持了NETs可能是SAH的潜在治疗靶点的想法。
Neuroinflammation is closely associated with poor prognosis in patients with subarachnoid hemorrhage (SAH). The purpose of this study was to investigate the role of neutrophil extracellular traps (NETs), which are important regulators of sterile inflammation, in SAH. In this study, markers of NET formation, quantified by the level of citrullinated histone H3 (CitH3), were significantly increased after SAH and correlated with SAH severity. CitH3 peaked at 12 h in peripheral blood and at 24 h in the brain. Administration of the peptidyl arginine deiminase 4 (PAD4) selective antagonist GSK484 substantially attenuated SAH-induced brain edema and neuronal injury. Moreover, the benefit of NET inhibition was also confirmed by DNAse I treatment and neutrophil depletion. Mechanistically, NETs markedly exacerbated microglial inflammation in vitro. NET formation aggravated neuroinflammation by promoting microglial activation and increased the levels of TNF-α, IL-1β, and IL-6, while inhibiting NETs demonstrated anti-inflammatory effects by decreasing the levels of these proinflammatory factors. Moreover, neurogenic pulmonary edema (NPE), a severe nonneurological complication after SAH, is associated with a high level of NET formation. However, GSK484 effectively inhibited the formation of NETs in the lungs of NPE mice, thereby preventing the diffusion of neutrophilic infiltration and attenuating the swelling of the alveolar interstitium. In conclusion, NETs promoted neuroinflammation after SAH, while pharmacological inhibition of PAD4-NETs could reduce the inflammatory damage caused by SAH. These results supported the idea that NETs might be potential therapeutic targets for SAH.