Microglial Nrf2-mediated lipid and iron metabolism reprogramming promotes remyelination during white matter ischemia

Hang Zhang; Sheng Yang; Yi-Lin Lu; Luo-Qi Zhou; Ming-Hao Dong; Yun-Hui Chu; Xiao-Wei Pang; Lian Chen; Lu-Lu Xu; Lu-Yang Zhang; Li-Fang Zhu; Ting Xu; Wei Wang; Ke Shang; Dai-Shi Tian; Chuan Qin

doi:10.1016/j.redox.2024.103473

Microglial Nrf2-mediated lipid and iron metabolism reprogramming promotes remyelination during white matter ischemia

Redox Biol. 2024 Dec 18:79:103473. doi: 10.1016/j.redox.2024.103473. Online ahead of print.

Authors

Hang Zhang¹, Sheng Yang¹, Yi-Lin Lu¹, Luo-Qi Zhou¹, Ming-Hao Dong¹, Yun-Hui Chu¹, Xiao-Wei Pang¹, Lian Chen¹, Lu-Lu Xu¹, Lu-Yang Zhang¹, Li-Fang Zhu¹, Ting Xu², Wei Wang¹, Ke Shang³, Dai-Shi Tian⁴, Chuan Qin⁵

Affiliations

¹ Department 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.
² Guangdong Province Key Laboratory of Brain Function and Disease, Department of Physiology and Pain Research Center, Zhongshan Medical School, Sun Yat-sen University, 74 Zhongshan Road 2, Guangzhou, 510080, PR China.
³ Department 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. Electronic address: kay_sang@hust.edu.cn.
⁴ Department 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. Electronic address: tiands@tjh.tjmu.edu.cn.
⁵ Department 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. Electronic address: chuanqin@tjh.tjmu.edu.cn.

PMID: 39718294
DOI: 10.1016/j.redox.2024.103473

Abstract

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 Cx3cr1^CreER 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.

Keywords: Chronic cerebral hypoperfusion; Ferroptosis; Lipid metabolism; Microglia; Nrf2; Oxidative stress.