Extracellular Mitochondria Activate Microglia and Contribute to Neuroinflammation in Traumatic Brain Injury
Extracellular Mitochondria Activate Microglia and Contribute to Neuroinflammation in Traumatic Brain Injury
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DOI：
10.1007/s12640-022-00566-8
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发表时间：
2022-09
影响因子：
3.7
通讯作者：
Chaonan Zhang;Chuan Liu;Fanjian Li;Mutian Zheng;Yafan Liu;Lei Li;Huaijin Yang;Shu Zhang
中科院分区：
文献类型：
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作者：
Chaonan Zhang;Chuan Liu;Fanjian Li;Mutian Zheng;Yafan Liu;Lei Li;Huaijin Yang;Shu Zhang
创伤性脑损伤(TBI)所致的神经炎症与患者的不良预后和高死亡率密切相关，对有效的临床干预措施的需求尚未得到满足。一系列的原因和传播因素已被确定为引起脑外伤所致的神经炎症。其中包括受损的脑细胞、内皮细胞和血小板释放的细胞微泡。在以前的研究中，我们已经提出，细胞微泡可以从损伤的脑组织中释放出来，导致消耗性凝血障碍。细胞外线粒体占这些微泡的55.2%，并诱导氧化还原依赖的血小板促凝活性，从而导致创伤性脑损伤引起的凝血和炎症。这导致了一种假设，即代谢活跃的细胞外线粒体有助于创伤性脑损伤的神经炎症，而不是与它们的促凝血活性无关。在这里，我们发现这些细胞外线粒体诱导了小胶质细胞M1型致炎表型的极化，加重了神经炎症，并以一种ROS依赖的方式介导了脑水肿。此外，在体外实验中，ROS抑制剂N-乙基马来酰亚胺(NEM)可减轻ROS的影响。这些结果揭示了细胞外线粒体的一种新的促炎活性，可能有助于创伤性脑损伤相关的神经炎症。
Traumatic brain injury (TBI)-induced neuroinflammation is closely associated with poor outcomes and high mortality in affected patients, with unmet needs for effective clinical interventions. A series of causal and disseminating factors have been identified to cause TBI-induced neuroinflammation. Among these are cellular microvesicles released from injured cerebral cells, endothelial cells, and platelets. In previous studies, we have put forward that cellular microvesicles can be released from injured brains that induce consumptive coagulopathy. Extracellular mitochondria accounted for 55.2% of these microvesicles and induced a redox-dependent platelet procoagulant activity that contributes to traumatic brain injury–induced coagulopathy and inflammation. These lead to the hypothesis that metabolically active extracellular mitochondria contribute to the neuroinflammation in traumatic brain injury, independent of their procoagulant activity. Here, we found that these extracellular mitochondria induced polarization of microglial M1-type pro-inflammatory phenotype, aggravating neuroinflammation, and mediated cerebral edema in a ROS-dependent manner. In addition, the effect of ROS can be alleviated by ROS inhibitorN-ethylmaleimide (NEM) in vitro experiments. These results revealed a novel pro-inflammatory activity of extracellular mitochondria that may contribute to traumatic brain injury–associated neuroinflammation.