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Ferroptosis drives immune-mediated neurodegeneration in multiple sclerosis

Cellular & Molecular Immunology volume 20, pages 112–113 (2023)Cite this article

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One of the leading issues in multiple sclerosis (MS) research is the lack of understanding regarding the triggers of neurodegeneration. While demyelination is a major feature in MS, the degeneration of gray matter neurons contributes to major changes in patient function, but the mechanisms driving this neuronal loss are unknown. In exciting research published by Luoqian et al. [1] in the December issue of Cellular and Molecular Immunology, new insights have shown an important contribution of ferroptosis to T-cell-mediated neurodegeneration in the common animal model of MS, ‘experimental autoimmune encephalomyelitis’ (EAE). Although a relationship between ferroptosis and T-cell activation has been reported in other disorders, this is the first discovery of a link between abnormal iron homeostasis and T-cell infiltration in MS. In addition, the authors found that unlike other studies on ferroptosis-T-cell interactions [2, 3], ferroptotic activation of T cells in EAE, and potentially MS, involved the infiltration and activation of CD4+ T cells, rather than CD8+ cells. Moreover, in this study, ferroptosis was a key driver of T-cell activation rather than the opposite interaction where CD8 + cells drive ferroptosis [3]. The research also mapped a key role for Acsl4 in the early stages of ferroptosis-T-cell-mediated neurodegeneration. Acsl4 converts free long-chain fatty acids into fatty acyl-CoA esters and has been identified as a central contributor to ferroptotic processes [4]. This study has mapped a major new pathway potentially leading to neurodegeneration in MS, and this opens the possibility of new therapeutic approaches to treat MS based on iron targeting as the authors describe in their final experiments.

Abnormal iron homeostasis in the brain reportedly contributes to several major neurological disorders, including Parkinson’s disease and potentially MS [5]. As reviewed previously [6] and confirmed in this study, iron levels in the spinal cord of EAE mice, modeling MS, showed substantial accumulation (~250% compared to healthy mice), without changes in other transition metals. However, in an interesting twist to the outcomes described by Luoqian et al. [1], this elevated iron was not required to initiate the ferroptotic pathway and subsequent T-cell activation in EAE mice. It appears that there are already early abnormal iron changes in the EAE mouse spinal cord and/or brain that are sufficient to contribute to ferroptotic activation, with the accumulation of iron occurring later in the disease process, potentially leading to an amplifying process.

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  1. Mental Health and Neuroscience, QIMR Berghofer Medical Research Institute, Herston, Qld, 4006, Australia

    Anthony R. White

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Correspondence to Anthony R. White.

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White, A.R. Ferroptosis drives immune-mediated neurodegeneration in multiple sclerosis. Cell Mol Immunol 20, 112–113 (2023). https://doi.org/10.1038/s41423-022-00941-7

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