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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
CIRBP mediates hypoxia-induced mitochondrial metabolic reprogramming in microglia to regulate polarization and
Yuchen Wang1, Ruize Ping2, Xiyuan Huang3
1Ministry of Education Key Laboratory of Hazard Assessment and Control in Special Operational Environments; Shaanxi Provincial Key Laboratory of Environmental Health Hazard Assessment and Protection, Shaanxi Provincial Key Laboratory of Free Radical Biology and Medicine, School of Preventive Medicine, Fourth Military Medical University, No. 169 Chang Le West Rd., Xi'an, Shaanxi 710032, China; Cadet Regiment, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
Abstract:
Exposure to high-altitude hypoxia can lead to anxiety-like behaviors, social issues, and other dysfunctions of the central nervous system (CNS), but the molecular mechanisms behind these effects are not fully understood. Microglial M1 polarization and changes in mitochondrial metabolism are crucial in hypoxic brain injury. The cold-inducible RNA-binding protein (CIRBP) is known to regulate mitochondrial balance and inflammatory responses. However, its role in hypoxia-induced microglial metabolic changes, polarization issues, and anxiety-like behaviors is still unclear. This study established an in vivo mouse model of high-altitude hypoxia, an in vitro hypoxic injury model of BV2 microglia, and an in vitro neuronal intervention model with microglia-derived conditioned medium. Integrating in vivo and in vitro experimental designs, we further systematically elucidated the potential molecular mechanisms underlying hypoxic brain injury. Findings indicated that high-altitude hypoxic exposure led to anxiety-like behaviors, social dysfunction, and neuronal and synaptic damage in the hippocampal CA1 region of mice. Hypoxia first triggered mitochondrial metabolic reprogramming in microglia, characterized by inhibition of oxidative phosphorylation, decreased ATP production, and accumulation of reactive oxygen species (ROS) and lactate, which subsequently drove the conversion to the M1 pro-inflammatory phenotype. Inhibition of microglial activation by minocycline significantly reversed hypoxia-induced synaptic damage. At the molecular level, hypoxia downregulated CIRBP expression in microglia. Overexpression of CIRBP in microglia ameliorated mitochondrial metabolic dysfunction and regulated microglial polarization, while knockdown of CIRBP in microglia exacerbated these abnormalities. Targeted overexpression of CIRBP in microglia within the hippocampal CA1 region significantly attenuated hypoxia-induced neuronal damage and behavioral abnormalities. This study elucidates a novel mechanism by which CIRBP in microglia mediates hypoxic brain injury, offering a potential therapeutic target for neuropsychiatric disorders associated with high-altitude hypoxia.
Insights
High-altitude hypoxia causes anxiety and brain damage by altering microglial metabolism and promoting M1 polarization. Cold-inducible RNA-binding protein (CIRBP) in microglia protects against these effects, offering a potential therapeutic target.
Area of Science:
- Neuroscience
- Cellular Biology
- Molecular Medicine
Background:
- High-altitude hypoxia induces central nervous system (CNS) dysfunction, including anxiety-like behaviors.
- Microglial M1 polarization and altered mitochondrial metabolism are key factors in hypoxic brain injury.
- The role of cold-inducible RNA-binding protein (CIRBP) in these hypoxia-induced changes is not well understood.
Purpose of the Study:
- To investigate the molecular mechanisms of high-altitude hypoxia-induced brain injury, focusing on microglial metabolism, polarization, and the role of CIRBP.
- To elucidate how CIRBP influences microglial responses to hypoxia and subsequent neuronal damage.
Main Methods:
- Established in vivo mouse models of high-altitude hypoxia and in vitro models using BV2 microglia and neuronal co-cultures.
- Analyzed microglial mitochondrial metabolism, M1 polarization, and CIRBP expression under hypoxic conditions.
- Utilized gene manipulation (overexpression and knockdown) of CIRBP in microglia and assessed behavioral and neuronal outcomes.
Main Results:
- High-altitude hypoxia induced anxiety-like behaviors, social dysfunction, and hippocampal CA1 neuronal/synaptic damage in mice.
- Hypoxia reprogrammed microglial mitochondrial metabolism, inhibiting oxidative phosphorylation and increasing ROS and lactate, driving M1 polarization.
- CIRBP downregulation in microglia exacerbated these effects, while CIRBP overexpression ameliorated them, protecting against neuronal damage and behavioral deficits.
Conclusions:
- CIRBP in microglia plays a protective role against hypoxia-induced brain injury by regulating mitochondrial metabolism and M1 polarization.
- Targeting CIRBP in microglia presents a novel therapeutic strategy for neuropsychiatric disorders linked to high-altitude hypoxia.
