Abstract
Despite the large number of immunomodulatory or immunosuppressive treatments available to treat relapsing–remitting multiple sclerosis (MS), treatment of the progressive phase of the disease has not yet been achieved. This lack of successful treatment approaches is caused by our poor understanding of the mechanisms driving disease progression. Emerging concepts suggest that a combination of persisting focal and diffuse inflammation within the CNS and a gradual failure of compensatory mechanisms, including remyelination, result in disease progression. Therefore, promotion of remyelination presents a promising intervention approach. However, despite our increasing knowledge regarding the cellular and molecular mechanisms regulating remyelination in animal models, therapeutic increases in remyelination remain an unmet need in MS, which suggests that mechanisms of remyelination and remyelination failure differ fundamentally between humans and demyelinating animal models. New and emerging technologies now allow us to investigate the cellular and molecular mechanisms underlying remyelination failure in human tissue samples in an unprecedented way. The aim of this Review is to summarize our current knowledge regarding mechanisms of remyelination and remyelination failure in MS and in animal models of the disease, identify open questions, challenge existing concepts, and discuss strategies to overcome the translational roadblock in the field of remyelination-promoting therapies.
Key points
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Promotion of remyelination is an unmet therapeutic need in multiple sclerosis.
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Animal models only partially reflect the human pathology of multiple sclerosis.
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The relationship between inflammation and remyelination is still unsolved.
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New models are needed to more precisely mimic remyelination in multiple sclerosis.
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Acknowledgements
The study was supported by the German Research Foundation (SFB128-B07 and KU1477/11-1 to T.K.; SFB128-A08 and SFB1009 A03 to L.K.) and the Interdisciplinary Center for Clinical Research Münster (KuT3/007/20 to T.K.).
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L.K. received compensation for serving on Scientific Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Genzyme, Horizon, Janssen, Merck Serono, Novartis, Roche and Viatris. She received speaker honoraria and travel support from Bayer, Biogen, Bristol-Myers Squibb, Genzyme, Grifols, Merck Serono, Novartis, Roche, Santhera and Teva. She receives research support from the German Research Foundation, the Interdisciplinary Center for Clinical Research (IZKF) Münster, IMF Münster, Biogen, Immunic AG, Novartis and Merck Serono. J.A. has no competing interests. T.K. received research funding from the German Research Foundation, IZKF Münster, National MS Society, Progressive MS Alliance, European Commission (H2020-MSCA-ITN-2018) and Novartis. She received compensation for serving on scientific advisory boards (Novartis) and speaker honoraria from Biogen, Novartis and Roche.
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Glossary
- Inflammaging
-
Chronic, sterile, low-grade inflammation involving the innate immune system, which accelerates the physiological ageing process.
- M1-polarized myeloid cells
-
Macrophages and microglial cells activated by LPS and cytokines such as IFNγ that contribute to inflammation, host defence and tumour cell elimination.
- M2-polarized myeloid cells
-
Macrophages and microglial cells activated by cytokines, such as IL-4 and IL-13, that contribute to tissue repair, angiogenesis and immune modulation.
- Magnetization transfer ratio
-
Magnetic imaging technique used for the evaluation of myelin content in the CNS.
- Major histocompatibility complex (MHC) class I molecules
-
Molecules expressed on all nucleated cells that present peptides derived from cytosolic proteins to elicit an immune response via cytotoxic CD8+ T cells.
- MHC class II molecules
-
Molecules expressed on professional antigen-presenting cells that present extracellular peptides to elicit an immune response via activation of CD4+ T helper cells.
- Micropillar array
-
High-throughput screening platform where small, standardized pillars serve as ‘axon-like’ structures to enable concentric wrapping by myelin sheaths.
- Normal-appearing white matter
-
Brain areas without focal demyelination.
- Shadow plaques
-
Completely remyelinated multiple sclerosis lesions.
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Klotz, L., Antel, J. & Kuhlmann, T. Inflammation in multiple sclerosis: consequences for remyelination and disease progression. Nat Rev Neurol 19, 305–320 (2023). https://doi.org/10.1038/s41582-023-00801-6
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DOI: https://doi.org/10.1038/s41582-023-00801-6
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