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

IF 10.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology Pub Date : 2025-02-01 DOI:10.1016/j.redox.2024.103473

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

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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.

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小胶质细胞nrf2介导的脂质和铁代谢重编程促进白质缺血时的髓鞘再生。

背景：氧化应激和小胶质细胞激活是缺血性脑白质损伤的重要病理机制。小胶质细胞作为大脑中的常驻免疫细胞，是发生氧化应激反应的主要细胞。然而，小胶质细胞氧化应激在脑白质缺血过程中的作用和分子机制尚不清楚。方法：在不同时间点对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活化。流式细胞分选和转录组测序相结合，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Cx3cr1CreER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。结果：我们的研究发现核因子红细胞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Nrf2短暂上调表达的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小胶质细胞的脂质过氧化和铁下垂，并降低抗氧化功能。通过药物或基因刺激Nrf2表达的小胶质细胞，由于脂质和铁代谢重编程，表现出对铁凋亡的增强抗性和对髓鞘形成的促进再生特性。结论：慢性脑灌注不足时，nrf2介导的抗氧化反应在小胶质细胞诱导的代谢紊乱和铁下沉中减弱。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。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Redox Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-

CiteScore

19.90

自引率

3.50%

发文量

318

审稿时长

25 days

期刊介绍： Redox Biology is the official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe. It is also affiliated with the International Society for Free Radical Research (SFRRI). This journal serves as a platform for publishing pioneering research, innovative methods, and comprehensive review articles in the field of redox biology, encompassing both health and disease. Redox Biology welcomes various forms of contributions, including research articles (short or full communications), methods, mini-reviews, and commentaries. Through its diverse range of published content, Redox Biology aims to foster advancements and insights in the understanding of redox biology and its implications.