Abstract
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 inhibitor N-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.
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Acknowledgements
This study is supported by the Young Scientists Award 82022020 from the National Natural Science Foundation of China (ZLZ), the National Natural Science Foundation of China (81971176 (ZLZ), 81930031, 81720108015 (JNZ)), the Natural Science Foundation of Tianjin City (18JCQNJC81000 (HTR)), the Tianjin Research Innovation Project for Postgraduate Students (2019YJSS183 (CNZ)), and the Key Laboratory of Central Nerve Injury Repair and Regeneration co-constructed by Province and Ministry.
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JZ, YF, and ZZ conceived the manuscript. CZ wrote the manuscript. CL and HG prepared the illustrations. CZ, CL, FL, MZ, YL, HY, and LL performed the experiments. SZ, CW, HR, YL, FL, and YL analyzed the data. All authors read and approved the final version of the manuscript prior to submission.
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Zhang, C., Liu, C., Li, F. et al. Extracellular Mitochondria Activate Microglia and Contribute to Neuroinflammation in Traumatic Brain Injury. Neurotox Res 40, 2264–2277 (2022). https://doi.org/10.1007/s12640-022-00566-8
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DOI: https://doi.org/10.1007/s12640-022-00566-8