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Published on: March 26, 2015
Microglial Nrf2-mediated lipid and iron metabolism reprogramming promotes remyelination during white matter ischemia
Hang Zhang1, Sheng Yang1, Yi-Lin Lu1
1Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, PR China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
Background:
Oxidative stress and microglial activation are critical pathomechanisms in ischemic white matter injury. Microglia, as resident immune cells in the brain, are the main cells undergoing oxidative stress response. However, the role and molecular mechanism of oxidative stress in microglia have not been clearly elucidated during white matter ischemia.
Methods:
Extensive histological analysis of the corpus callosum was performed in BCAS mice at different time points to assess white matter injury, oxidative stress and microglial activation. Flow cytometric sorting and transcriptomic sequencing were combined to explore the underlying mechanisms regulating microglial oxidative stress and functional phenotypes. The expression of critical molecule in microglia was regulated using Cx3cr1CreER mice and clinical-stage drugs to assess its effect on white matter injury and cognitive function.
Results:
Our study identified nuclear factor erythroid-2 related factor 2 (Nrf2) as a key transcription factor regulating oxidative stress and functional phenotype in microglia. Interestingly, we found that the sustained decrease in transiently upregulated expression of Nrf2 following chronic cerebral hypoperfusion resulted in abnormal microglial activation and white matter injury. In addition, high loads of myelin debris promoted lipid peroxidation and ferroptosis in microglia with diminished antioxidant function. Microglia with pharmacologically or genetically stimulated Nrf2 expression exhibited enhanced resistance to ferroptosis and pro-regenerative properties to myelination due to lipid and iron metabolism reprogramming.
Conclusion:
Weakened Nrf2-mediated antioxidant responses in microglia induced metabolic disturbances and ferroptosis during chronic cerebral hypoperfusion. Targeted enhancement of Nrf2 expression in microglia may be a potential therapeutic strategy for ischemic white matter injury.
Insights
Weakened antioxidant responses in microglia contribute to white matter injury. Enhancing nuclear factor erythroid-2 related factor 2 (Nrf2) in microglia shows therapeutic potential for ischemic white matter damage.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Oxidative stress and microglial activation are key factors in ischemic white matter injury.
- Microglia, the brain's resident immune cells, are central to oxidative stress responses, but their specific role in white matter ischemia remains unclear.
Purpose of the Study:
- To elucidate the role and molecular mechanisms of oxidative stress in microglia during white matter ischemia.
- To investigate the therapeutic potential of targeting microglial oxidative stress pathways.
Main Methods:
- Histological analysis of the corpus callosum in BCAS mice to evaluate white matter injury, oxidative stress, and microglial activation.
- Flow cytometry and transcriptomic sequencing to identify mechanisms regulating microglial oxidative stress and function.
- Genetic and pharmacological manipulation of nuclear factor erythroid-2 related factor 2 (Nrf2) expression in microglia to assess impact on white matter injury and cognitive function.
Main Results:
- Nuclear factor erythroid-2 related factor 2 (Nrf2) was identified as a critical transcription factor for microglial oxidative stress and phenotype.
- A decrease in Nrf2 expression following chronic cerebral hypoperfusion led to abnormal microglial activation and white matter injury.
- Myelin debris exacerbated lipid peroxidation and ferroptosis in microglia; enhanced Nrf2 expression improved ferroptosis resistance and promoted regeneration.
Conclusions:
- Impaired Nrf2-mediated antioxidant responses in microglia contribute to metabolic dysfunction and ferroptosis in chronic cerebral hypoperfusion.
- Targeted enhancement of Nrf2 in microglia presents a promising therapeutic strategy for ischemic white matter injury.
