The NLRP3 inflammasome is a critical mediator of several vascular diseases through positive regulation of proinflammatory pathways. In this study, we defined the role of NLRP3 in both the acute and delayed phases following subarachnoid hemorrhage (SAH). SAH is associated with devastating early brain injury (EBI) in the acute phase, and those that survive remain at risk for developing delayed cerebral ischemia (DCI) due to cerebral vasospasm. Current therapies are not effective in preventing the morbidity and mortality associated with EBI and DCI. NLRP3 activation is known to drive IL-1β production and stimulate microglia reactivity, both hallmarks of SAH pathology; thus, we hypothesized that inhibition of NLRP3 could alleviate SAH-induced vascular dysfunction and functional deficits. We studied NLRP3 in an anterior circulation autologous blood injection model of SAH in mice. Mice were randomized to either sham surgery + vehicle, SAH + vehicle, or SAH + MCC950 (a selective NLRP3 inhibitor). The acute phase was studied at 1 day post-SAH and delayed phase at 5 days post-SAH. NLRP3 inhibition improved outcomes at both 1 and 5 days post-SAH. In the acute (1 day post-SAH) phase, NLRP3 inhibition attenuated cerebral edema, tight junction disruption, microthrombosis, and microglial reactive morphology shift. Further, we observed a decrease in apoptosis of neurons in mice treated with MCC950. NLRP3 inhibition also prevented middle cerebral artery vasospasm in the delayed (5 days post-SAH) phase and blunted SAH-induced sensorimotor deficits. We demonstrate a novel association between NLRP3-mediated neuroinflammation and cerebrovascular dysfunction in both the early and delayed phases after SAH. MCC950 and other NLRP3 inhibitors could be promising tools in the development of therapeutics for EBI and DCI.

中文翻译：

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NLRP3抑制可减轻蛛网膜下腔出血后的早期脑损伤和迟发性脑血管痉挛


NLRP3 炎症小体通过对促炎途径进行正向调节，是多种血管疾病的关键介质。在这项研究中，我们定义了 NLRP3 在蛛网膜下腔出血 (SAH) 急性期和迟发期的作用。 SAH 与急性期的破坏性早期脑损伤 (EBI) 相关，而那些存活下来的人仍然面临因脑血管痉挛而发生迟发性脑缺血 (DCI) 的风险。目前的疗法不能有效预防与 EBI 和 DCI 相关的发病率和死亡率。 NLRP3 激活已知可驱动 IL-1β 产生并刺激小胶质细胞反应性，这都是 SAH 病理学的标志；因此，我们假设抑制NLRP3可以减轻SAH引起的血管功能障碍和功能缺陷。我们在小鼠 SAH 前循环自体血液注射模型中研究了 NLRP3。小鼠被随机分为假手术+载体、SAH+载体或SAH+MCC950（一种选择性NLRP3抑制剂）。急性期在 SAH 后 1 天进行研究，延迟期在 SAH 后 5 天进行研究。 NLRP3 抑制可改善 SAH 后 1 天和 5 天的结果。在急性期（SAH 后 1 天），NLRP3 抑制可减轻脑水肿、紧密连接破坏、微血栓形成和小胶质细胞反应性形态转变。此外，我们观察到接受 MCC950 治疗的小鼠神经细胞凋亡减少。 NLRP3 抑制还可以预防延迟期（SAH 后 5 天）的大脑中动脉血管痉挛，并减弱 SAH 诱导的感觉运动缺陷。我们证明了 SAH 后早期和延迟期 NLRP3 介导的神经炎症与脑血管功能障碍之间的新关联。 MCC950 和其他 NLRP3 抑制剂可能成为开发 EBI 和 DCI 疗法的有前景的工具。