NLRP3 inhibition attenuates early brain injury and delayed cerebral vasospasm after subarachnoid hemorrhage.
NLRP3 inhibition attenuates early brain injury and delayed cerebral vasospasm after subarachnoid hemorrhage.
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DOI：
10.1186/s12974-021-02207-x
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发表时间：
2021-07-20
影响因子：
9.3
通讯作者：
Hoh BL
中科院分区：
文献类型：
--
作者：
Dodd WS;Noda I;Martinez M;Hosaka K;Hoh BL
NLRP 3炎性体是几种血管疾病的关键介质，通过正向调节促炎途径。在这项研究中，我们确定了NLRP 3在蛛网膜下腔出血（SAH）后急性期和延迟期的作用。SAH与急性期的毁灭性早期脑损伤（EBI）相关，而存活的患者仍有因脑血管痉挛而发生迟发性脑缺血（DCI）的风险。目前的治疗不能有效预防EBI和DCI相关的发病率和死亡率。已知NLRP 3激活可驱动IL-1β产生并刺激小胶质细胞反应性，这两个都是SAH病理学的标志;因此，我们假设抑制NLRP 3可减轻SAH诱导的血管功能障碍和功能缺陷。我们在小鼠SAH的前循环自体血液注射模型中研究了NLRP 3。将小鼠随机分配至假手术+媒介物、SAH +媒介物或SAH + MCC 950（选择性NLRP 3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。NLRP 3抑制改善SAH后1天和5天的结果。在急性期（SAH后1天），NLRP 3抑制减轻脑水肿、紧密连接破坏、微血栓形成和小胶质细胞反应性形态学变化。此外，我们观察到用MCC 950处理的小鼠中神经元凋亡减少。NLRP 3抑制还防止了延迟期（SAH后5天）的大脑中动脉血管痉挛，并减弱了SAH诱导的感觉运动缺陷。我们证明了NLRP 3介导的神经炎症与SAH后早期和延迟期脑血管功能障碍之间的新关联。MCC 950和其他NLRP 3抑制剂可能是开发EBI和DCI治疗剂的有前途的工具。在线版本包含补充材料，可通过10.1186/s12974-021-02207-x获得。
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. The online version contains supplementary material available at 10.1186/s12974-021-02207-x.
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作者：
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