Deletion of Bak1 alleviates microglial necroptosis and neuroinflammation after experimental subarachnoid hemorrhage
Deletion of Bak1 alleviates microglial necroptosis and neuroinflammation after experimental subarachnoid hemorrhage
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DOI：
10.1111/jnc.15751
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发表时间：
2022-12
影响因子：
4.7
通讯作者：
Xiancheng Qiu;Qianke Tao;Li-hua Zhang;Chenghao Kuang;Yuke Xie;Lifang Zhang;Shigang Yin;Jianhua Peng;Yong Jiang
中科院分区：
文献类型：
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作者：
Xiancheng Qiu;Qianke Tao;Li-hua Zhang;Chenghao Kuang;Yuke Xie;Lifang Zhang;Shigang Yin;Jianhua Peng;Yong Jiang
小胶质细胞坏死性上闭加剧了神经退行性疾病，中枢神经系统（CNS）损伤，并表现出促炎过程，但其对蛛网膜下腔出血（SAH）的贡献尚不清楚。BCL - 2同源拮抗剂-杀伤蛋白（Bak1）是内源性细胞凋亡的关键调控分子，可通过调节线粒体通透性参与坏死坏死的病理过程。在本研究中，我们在体内和体外发现小胶质细胞在SAH后发生坏死下垂。Western blot结果显示，SAH后24小时Bak1升高。腺相关病毒敲除Bak1可减轻小鼠SAH后的小胶质坏死，减轻神经炎症，并改善神经功能。此外，氧合血红蛋白（10 μM）诱导BV2小胶质细胞坏死，增加Bak1表达，介导促炎表型转化，加剧氧化应激和神经炎症。去除BV2 Bak1可以通过下调磷酸化伪激酶混合谱系激酶结构域样蛋白（p - MLKL）的表达，进而下调促炎表型基因的表达，从而减少坏死性坏死。RNA‐Seq显示，破坏BV2 Bak1下调多种免疫和炎症途径，并通过提高血栓反应蛋白1 （THBS1）的表达来改善细胞损伤。总之，我们确定了Bak1在SAH后小胶质细胞坏死和神经炎症中的关键调节作用。Bak1有望成为SAH治疗策略的潜在靶点。
Microglial necroptosis exacerbates neurodegenerative diseases, central nervous system (CNS) injury, and demonstrates a proinflammatory process, but its contribution to subarachnoid hemorrhage (SAH) is poorly characterized. BCL‐2 homologous antagonist‐killer protein (Bak1), a critical regulatory molecule of endogenous apoptosis, can be involved in the pathologic process of necroptosis by regulating mitochondrial permeability. In this study, we revealed microglia undergo necroptosis after SAH in vivo and vitro. Western blot revealed that Bak1 was elevated at 24 h after SAH. Knocked down of Bak1 by adeno‐associated virus attenuates microglial necroptosis, alleviates neuroinflammation, and improves neurologic function after SAH in mice. Furthermore, oxyhemoglobin (10 μM) induced necroptosis in BV2 microglia, increasing Bak1 expression and mediating proinflammatory phenotype transformation, exacerbating oxidative stress and neuroinflammation. Abrogating BV2 Bak1 could reduce necroptosis by down‐regulating the expression of phosphorylated pseudokinase mixed lineage kinase domain‐like protein (p‐MLKL), then down‐regulating proinflammatory phenotype gene expression. RNA‐Seq showed that disrupting BV2 Bak1 down‐regulates multiple immune and inflammatory pathways and ameliorates cell injury by elevating thrombospondin 1 (THBS1) expression. In summary, we identified a critical regulatory role for Bak1 in microglial necroptosis and neuroinflammation after SAH. Bak1 is expected to be a potential target for the treatment strategy of SAH.