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Extracellular Mitochondria Activate Microglia and Contribute to Neuroinflammation in Traumatic Brain Injury
Chaonan Zhang1,2, Chuan Liu1,2, Fanjian Li1,2
1Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China.
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.
Insights
Extracellular mitochondria from traumatic brain injury (TBI) promote neuroinflammation by activating microglial cells. This process, dependent on reactive oxygen species (ROS), contributes to brain swelling and poor patient outcomes.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Traumatic brain injury (TBI) triggers neuroinflammation, linked to poor patient outcomes and mortality.
- Cellular microvesicles, including extracellular mitochondria, are implicated in TBI pathogenesis.
- Previous work identified extracellular mitochondria's role in TBI-induced coagulopathy.
Purpose of the Study:
- To investigate the role of extracellular mitochondria in TBI-induced neuroinflammation, independent of coagulant activity.
- To determine if extracellular mitochondria directly contribute to microglial activation and cerebral edema.
Main Methods:
- Isolation and characterization of extracellular mitochondria from injured brain tissue.
- In vitro experiments assessing microglial M1 phenotype polarization.
- Evaluation of reactive oxygen species (ROS) production and mitigation using ROS inhibitors.
Main Results:
- Extracellular mitochondria induced M1-type microglial polarization, exacerbating neuroinflammation.
- Cerebral edema was mediated by extracellular mitochondria in a ROS-dependent manner.
- ROS inhibition using N-ethylmaleimide (NEM) alleviated these effects in vitro.
Conclusions:
- Extracellular mitochondria possess a novel pro-inflammatory activity in TBI.
- Metabolically active extracellular mitochondria contribute to TBI-associated neuroinflammation via ROS production.
- Targeting extracellular mitochondria or ROS may offer therapeutic strategies for TBI.
