Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage
Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage
复制标题
实验性蛛网膜下腔出血中 IFN 基因刺激物通过抑制 AMPK 信号介导神经炎症损伤
DOI：
10.1186/s12974-020-01830-4
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发表时间：
2020-05-25
影响因子：
9.3
通讯作者：
Chen, Gao
中科院分区：
文献类型：
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作者：
Peng, Yucong;Zhuang, Jianfeng;Chen, Gao
背景神经炎症与蛛网膜下腔出血(SAH)患者预后不良密切相关。本研究旨在探讨干扰素基因刺激物(STING)在蛛网膜下腔出血(SAH)中的作用。方法雄性C57BL/6J小鼠344只，采用血管内穿孔法制备蛛网膜下腔出血模型。分别于造模后30min和1h分别给予选择性刺痛拮抗剂C-176和刺痛激动剂CMA。为了探讨其可能的机制，在手术前30分钟侧脑室注射AMPK抑制剂化合物C。SAH后评估包括SAH评分、神经学检查、脑含水量、Western blotting、RT-PCR和免疫荧光。将氧合血红蛋白导入BV2细胞，建立SAH体外模型。结果STING主要分布于小胶质细胞，SAH后小胶质细胞STING表达明显增加。给予C-176可显著减轻SAH引起的脑水肿和神经元损伤。更重要的是，C-176显著缓解了SAH后的短期和持续性神经功能障碍。同时，刺痛激动剂CMA显著加重神经元损伤，加重神经功能损害。机械上，刺痛通过促进小胶质细胞活化和分化为M1表型而加重神经炎症，表现为小胶质细胞的形态变化，以及小胶质细胞M1标志物水平的增加，包括IL-1β、iNOS、IL-6、TNF-α、MCP-1和NLRP3炎症小体，而C-176具有强大的抗炎作用。然而，AMPK抑制剂化合物C逆转了C-176的上述作用，包括减轻神经炎症、减轻神经元损伤和改善神经功能，同时在体外也证实了AMPK信号在C-176介导的抗炎作用中的关键作用。结论小胶质细胞刺伤可导致SAH后神经细胞炎症反应，药物抑制作用至少部分通过激活AMPK信号途径减轻SAH所致的炎性损伤。这些数据支持了STING可能是SAH的潜在治疗靶点的观点。
Background Neuroinflammation is closely associated with the poor prognosis in subarachnoid hemorrhage (SAH) patients. This study was aimed to determine the role of stimulator of IFN genes (STING), an essential regulator to innate immunity, in the context of SAH. Methods A total of 344 male C57BL/6 J mice were subjected to endovascular perforation to develop a model of SAH. Selective STING antagonist C-176 and STING agonist CMA were administered at 30 min or 1 h post-modeling separately. To investigate the underlying mechanism, the AMPK inhibitor compound C was administered intracerebroventricularly at 30 min before surgery. Post-SAH assessments included SAH grade, neurological test, brain water content, western blotting, RT-PCR, and immunofluorescence. Oxygenated hemoglobin was introduced into BV2 cells to establish a SAH model in vitro. Results STING was mainly distributed in microglia, and microglial STING expression was significantly increased after SAH. Administration of C-176 substantially attenuated SAH-induced brain edema and neuronal injury. More importantly, C-176 significantly alleviated both short-term and persistent neurological dysfunction after SAH. Meanwhile, STING agonist CMA remarkably exacerbated neuronal injury and deteriorated neurological impairments. Mechanically, STING activation aggravated neuroinflammation via promoting microglial activation and polarizing into M1 phenotype, evidenced by microglial morphological changes, as well as the increased level of microglial M1 markers including IL-1 beta, iNOS, IL-6, TNF-alpha, MCP-1, and NLRP3 inflammasome, while C-176 conferred a robust anti-inflammatory effect. However, all the mentioned beneficial effects of C-176 including alleviated neuroinflammation, attenuated neuronal injury and the improved neurological function were reversed by AMPK inhibitor compound C. Meanwhile, the critical role of AMPK signal in C-176 mediated anti-inflammatory effect was also confirmed in vitro. Conclusion Microglial STING yielded neuroinflammation after SAH, while pharmacologic inhibition of STING could attenuate SAH-induced inflammatory injury at least partly by activating AMPK signal. These data supported the notion that STING might be a potential therapeutic target for SAH.