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Ferroptosis promotes T-cell activation-induced neurodegeneration in multiple sclerosis

Cellular & Molecular Immunology volume 19, pages 913–924 (2022)Cite this article

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Abstract

While many drugs are effective at reducing the relapse frequency of multiple sclerosis (MS), there is an unmet need for treatments that slow neurodegeneration resulting from secondary disease progression. The mechanism of neurodegeneration in MS has not yet been established. Here, we discovered a potential pathogenetic role of ferroptosis, an iron-dependent regulated cell death mechanism, in MS. We found that critical ferroptosis proteins (acyl-CoA synthetase long-chain family member 4, ACSL4) were altered in an existing genomic database of MS patients, and biochemical features of ferroptosis, including lipid reactive oxygen species (ROS) accumulation and mitochondrial shrinkage, were observed in the experimental autoimmune encephalitis (EAE) mouse model. Targeting ferroptosis with ferroptosis inhibitors or reducing ACSL4 expression improved the behavioral phenotypes of EAE mice, reduced neuroinflammation, and prevented neuronal death. We found that ferroptosis was an early event in EAE, which may promote T-cell activation through T-cell receptor (TCR) signaling in vitro and in vivo. These data indicate that ferroptosis may be a potential target for treating MS.

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Data supporting this study are available from the corresponding authors upon request.

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Acknowledgements

This work was supported by the National Key Research and Development Project of China (2019YFA0110201), the National Natural Science Foundation of China (82071191, 81801182, 82025002, 32000724, 81871232), and the National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (2020YJC01, Z2021LC001).

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  1. These authors contributed equally: Jinyuan Luoqian, Wenyong Yang, Xulong Ding.

Authors and Affiliations

  1. Department of Neurology and Center for Immunology and Hematology, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China

    Jinyuan Luoqian, Wenyong Yang, Xulong Ding, Qing-zhang Tuo, Zheng Xiang, Zhaoyue Zheng, Yu-jie Guo, Li Li, Pengbo Guan, Biao Dong, Huiyuan Zhang, Hongbo Hu & Peng Lei

  2. Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia

    Scott Ayton

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Contributions

Contribution: PL and HH conceived and raised funds for the study. PL supervised the overall project. JY-LQ performed the in vivo studies with supervision from PL and Q-zT. X-lD, W-yY, LL, and P-bG performed the in vitro studies with supervision from HZ and HH. X-lD analyzed the RNA-seq data with supervision from PL. ZX and Z-yZ prepared the AAV-related experiments with supervision from BD. JY-LQ, PL and HH integrated the data and wrote the drafts of the paper. All authors edited the paper.

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Correspondence to Hongbo Hu or Peng Lei.

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Luoqian, J., Yang, W., Ding, X. et al. Ferroptosis promotes T-cell activation-induced neurodegeneration in multiple sclerosis. Cell Mol Immunol 19, 913–924 (2022). https://doi.org/10.1038/s41423-022-00883-0

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