Microglial Nrf2-mediated lipid and iron metabolism reprogramming promotes remyelination during white matter ischemia
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 h...
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Elsevier
2025-02-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Hang Zhang |
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| description | 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. |
| format | Article |
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| institution | Kabale University |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
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| series | Redox Biology |
| spelling | doaj-art-d4ad0016f6304deba17a116f7b3ef8a52025-01-14T04:12:12ZengElsevierRedox Biology2213-23172025-02-0179103473Microglial Nrf2-mediated lipid and iron metabolism reprogramming promotes remyelination during white matter ischemiaHang Zhang0Sheng Yang1Yi-Lin Lu2Luo-Qi Zhou3Ming-Hao Dong4Yun-Hui Chu5Xiao-Wei Pang6Lian Chen7Lu-Lu Xu8Lu-Yang Zhang9Li-Fang Zhu10Ting Xu11Wei Wang12Ke Shang13Dai-Shi Tian14Chuan Qin15Department 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaGuangdong 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 ChinaDepartment 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 ChinaDepartment 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; Corresponding author. Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.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; Corresponding author. Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.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; Corresponding author. Department of Neurology, Tongji Hospital, 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.http://www.sciencedirect.com/science/article/pii/S2213231724004518Chronic cerebral hypoperfusionOxidative stressMicrogliaNrf2Lipid metabolismFerroptosis |
| spellingShingle | 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 Microglial Nrf2-mediated lipid and iron metabolism reprogramming promotes remyelination during white matter ischemia Redox Biology Chronic cerebral hypoperfusion Oxidative stress Microglia Nrf2 Lipid metabolism Ferroptosis |
| title | Microglial Nrf2-mediated lipid and iron metabolism reprogramming promotes remyelination during white matter ischemia |
| title_full | Microglial Nrf2-mediated lipid and iron metabolism reprogramming promotes remyelination during white matter ischemia |
| title_fullStr | Microglial Nrf2-mediated lipid and iron metabolism reprogramming promotes remyelination during white matter ischemia |
| title_full_unstemmed | Microglial Nrf2-mediated lipid and iron metabolism reprogramming promotes remyelination during white matter ischemia |
| title_short | Microglial Nrf2-mediated lipid and iron metabolism reprogramming promotes remyelination during white matter ischemia |
| title_sort | microglial nrf2 mediated lipid and iron metabolism reprogramming promotes remyelination during white matter ischemia |
| topic | Chronic cerebral hypoperfusion Oxidative stress Microglia Nrf2 Lipid metabolism Ferroptosis |
| url | http://www.sciencedirect.com/science/article/pii/S2213231724004518 |
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