Zhang Hang, Yang Sheng, Lu Yi-Lin, Zhou Luo-Qi, Dong Ming-Hao, Chu Yun-Hui, Pang Xiao-Wei, Chen Lian, Xu Lu-Lu, Zhang Lu-Yang, Zhu Li-Fang, Xu Ting, Wang Wei, Shang Ke, Tian Dai-Shi, Qin Chuan
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.
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.
Redox Biol. 2025 Feb;79:103473. doi: 10.1016/j.redox.2024.103473. Epub 2024 Dec 18.
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.
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 mice and clinical-stage drugs to assess its effect on white matter injury and cognitive function.
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.
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.
氧化应激和小胶质细胞激活是缺血性白质损伤的关键病理机制。小胶质细胞作为脑内的常驻免疫细胞，是经历氧化应激反应的主要细胞。然而，在白质缺血过程中，氧化应激在小胶质细胞中的作用和分子机制尚未明确阐明。
在不同时间点对双侧颈总动脉永久结扎（BCAS）小鼠的胼胝体进行广泛的组织学分析，以评估白质损伤、氧化应激和小胶质细胞激活情况。将流式细胞术分选和转录组测序相结合，以探索调节小胶质细胞氧化应激和功能表型的潜在机制。使用Cx3cr1小鼠和临床阶段药物调节小胶质细胞中关键分子的表达，以评估其对白质损伤和认知功能的影响。
我们的研究确定核因子红细胞2相关因子2（Nrf2）是调节小胶质细胞氧化应激和功能表型的关键转录因子。有趣的是，我们发现慢性脑灌注不足后短暂上调的Nrf2表达持续下降，导致小胶质细胞异常激活和白质损伤。此外，高负荷的髓磷脂碎片促进了小胶质细胞的脂质过氧化和铁死亡，同时抗氧化功能减弱。药理学或基因刺激Nrf2表达的小胶质细胞由于脂质和铁代谢重编程，表现出对铁死亡的抗性增强以及对髓鞘形成的促再生特性。
慢性脑灌注不足期间，小胶质细胞中Nrf2介导的抗氧化反应减弱，诱导了代谢紊乱和铁死亡。靶向增强小胶质细胞中Nrf2的表达可能是缺血性白质损伤的潜在治疗策略。
