CNS remyelination and inflammation: From basic mechanisms to therapeutic opportunities
Open accessAbstract
Remyelination, the myelin regenerative response that follows demyelination, restores saltatory conduction and function and sustains axon health. Its declining efficiency with disease progression in the chronic autoimmune disease multiple sclerosis (MS) contributes to the currently untreatable progressive phase of the disease. Although some of the bona fide myelin regenerative medicine clinical trials have succeeded in demonstrating proof-of-principle, none of these compounds have yet proceeded toward approval. There therefore remains a need to increase our understanding of the fundamental biology of remyelination so that existing targets can be refined and new ones discovered. Here, we review the role of inflammation, in particular innate immunity, in remyelination, describing its many and complex facets and discussing how our evolving understanding can be harnessed to translational goals.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The differentiation of local oligodendrocyte progenitor cells into actively myelinating oligodendrocytes is stimulated by innate immune cells.
“Recent data have indicated that the differentiation of local oligodendrocyte progenitor cells into actively myelinating oligodendrocytes is stimulated by innate immune cells.64-67”
From BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis (2025) · cites this paper as [67]
Cites
A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease
Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T. K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.018 · Cited by 5,493 · see citing works
Macrophages in Tissue Repair, Regeneration, and Fibrosis
Wynn, T. A., & Vannella, K. M. (2016) · Immunity · doi:10.1016/j.immuni.2016.02.015 · Cited by 4,481 · see citing works
Krasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O’Loughlin, E., Xu, Y., Fanek, Z., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.08.008 · Cited by 2,979 · see citing works
Hammond, T. R., Dufort, C., Dissing-Olesen, L., Giera, S., Young, A., Wysoker, A., Walker, A. J., Segel, M., Nemesh, J., Saunders, A., et al. (2018) · doi:10.1101/406140 · Cited by 2,225 · see citing works
Self-citationImmunopathology of multiple sclerosis
Dendrou, C. A., Fugger, L., & Friese, M. A. (2015) · Nature Reviews Immunology · doi:10.1038/nri3871 · Cited by 2,215 · see citing works
Astrocyte scar formation aids central nervous system axon regeneration
Anderson, M. A., Burda, J. E., Ren, Y., Ao, Y., O’Shea, T. M., Kawaguchi, R., Coppola, G., Khakh, B. S., Deming, T. J., & Sofroniew, M. V. (2016) · Nature · doi:10.1038/nature17623 · Cited by 1,851 · see citing works
M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination
Miron, V. E., Boyd, A., Zhao, J.-W., Yuen, T. J., Ruckh, J. M., Shadrach, J. L., van Wijngaarden, P., Wagers, A. J., Williams, A., Franklin, R. J. M., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3469 · Cited by 1,788 · see citing works
Self-citationDisease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration
Deczkowska, A., Keren-Shaul, H., Weiner, A., Colonna, M., Schwartz, M., & Amit, I. (2018) · Cell · doi:10.1016/j.cell.2018.05.003 · Cited by 1,474 · see citing works
Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution
Masuda, T., Sankowski, R., Staszewski, O., Böttcher, C., Amann, L., Sagar, Scheiwe, C., Nessler, S., Kunz, P., van Loo, G., et al. (2019) · Nature · doi:10.1038/s41586-019-0924-x · Cited by 1,310 · see citing works
TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease
Ulland, T. K., Song, W. M., Huang, S. C.-C., Ulrich, J. D., Sergushichev, A., Beatty, W. L., Loboda, A. A., Zhou, Y., Cairns, N. J., Kambal, A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.07.023 · Cited by 1,263 · see citing works
Astrocyte barriers to neurotoxic inflammation
Sofroniew, M. V. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3898 · Cited by 1,202 · see citing works
Microglial signatures and their role in health and disease
Butovsky, O., & Weiner, H. L. (2018) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0057-5 · Cited by 1,046 · see citing works
TNFα promotes proliferation of oligodendrocyte progenitors and remyelination
Arnett, H. A., Mason, J., Marino, M., Suzuki, K., Matsushima, G. K., & Ting, J. P.-Y. (2001) · Nature Neuroscience · doi:10.1038/nn738 · Cited by 1,012 · see citing works
Myelin Impairs CNS Remyelination by Inhibiting Oligodendrocyte Precursor Cell Differentiation
Kotter, M. R., Li, W.-W., Zhao, C., & Franklin, R. J. M. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.2615-05.2006 · Cited by 768 · see citing works
Self-citationThe spectrum of inflammatory responses
Medzhitov, R. (2021) · Science · doi:10.1126/science.abi5200 · Cited by 718 · see citing works
Zawadzka, M., Rivers, L. E., Fancy, S. P. J., Zhao, C., Tripathi, R., Jamen, F., Young, K., Goncharevich, A., Pohl, H., Rizzi, M., et al. (2010) · Cell stem cell · doi:10.1016/j.stem.2010.04.002 · Cited by 650 · see citing works
Self-citationRejuvenation of Regeneration in the Aging Central Nervous System
Ruckh, J. M., Zhao, J.-W., Shadrach, J. L., van Wijngaarden, P., Rao, T. N., Wagers, A. J., & Franklin, R. J. M. (2012) · Cell Stem Cell · doi:10.1016/j.stem.2011.11.019 · Cited by 649 · see citing works
Self-citationRegenerating CNS myelin — from mechanisms to experimental medicines
Franklin, R. J. M., & ffrench-Constant, C. (2017) · Nature Reviews Neuroscience · doi:10.1038/nrn.2017.136 · Cited by 647 · see citing works
Self-citationNeuronal vulnerability and multilineage diversity in multiple sclerosis
Schirmer, L., Velmeshev, D., Holmqvist, S., Kaufmann, M., Werneburg, S., Jung, D., Vistnes, S., Stockley, J. H., Young, A., Steindel, M., et al. (2019) · Nature · doi:10.1038/s41586-019-1404-z · Cited by 638 · see citing works
Self-citationHyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation
Back, S. A., Tuohy, T. M. F., Chen, H., Wallingford, N., Craig, A., Struve, J., Luo, N. L., Banine, F., Liu, Y., Chang, A., et al. (2005) · Nature Medicine · doi:10.1038/nm1279 · Cited by 612 · see citing works
Inefficient clearance of myelin debris by microglia impairs remyelinating processes
Lampron, A., Larochelle, A., Laflamme, N., Préfontaine, P., Plante, M.-M., Sánchez, M. G., Yong, V. W., Stys, P. K., Tremblay, M.-È., & Rivest, S. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20141656 · Cited by 595 · see citing works
Multiple sclerosis: Remyelination of nascent lesions: Remyelination of nascent lesions
Prineas, J. W., Barnard, R. O., Kwon, E. E., Sharer, L. R., & Cho, E. ‐. (1993) · Annals of Neurology · doi:10.1002/ana.410330203 · Cited by 574 · see citing works
Regulatory T cells promote myelin regeneration in the central nervous system
Dombrowski, Y., O'Hagan, T., Dittmer, M., Penalva, R., Mayoral, S. R., Bankhead, P., Fleville, S., Eleftheriadis, G., Zhao, C., Naughton, M., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4528 · Cited by 533 · see citing works
Self-citationTREM2 sustains microglial expansion during aging and response to demyelination
Poliani, P. L., Wang, Y., Fontana, E., Robinette, M. L., Yamanishi, Y., Gilfillan, S., & Colonna, M. (2015) · Journal of Clinical Investigation · doi:10.1172/jci77983 · Cited by 525 · see citing works
CD22 blockade restores homeostatic microglial phagocytosis in ageing brains
Pluvinage, J. V., Haney, M. S., Smith, B. A. H., Sun, J., Iram, T., Bonanno, L., Li, L., Lee, D. P., Morgens, D. W., Yang, A. C., et al. (2019) · Nature · doi:10.1038/s41586-019-1088-4 · Cited by 459 · see citing works
Progressive multiple sclerosis: from pathophysiology to therapeutic strategies
Faissner, S., Plemel, J. R., Gold, R., & Yong, V. W. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0035-2 · Cited by 459 · see citing works
Cignarella, F., Filipello, F., Bollman, B., Cantoni, C., Locca, A., Mikesell, R., Manis, M., Ibrahim, A., Deng, L., Benitez, B. A., et al. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02193-z · Cited by 392 · see citing works
Kotter, M. R., Setzu, A., Sim, F. J., Van Rooijen, N., & Franklin, R. J. M. (2001) · Glia · doi:10.1002/glia.1085 · Cited by 385 · see citing works
Self-citationThe pro-remyelination properties of microglia in the central nervous system
Lloyd, A. F., & Miron, V. E. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0184-2 · Cited by 381 · see citing works
Dynamics of oligodendrocyte generation in multiple sclerosis
Yeung, M. S. Y., Djelloul, M., Steiner, E., Bernard, S., Salehpour, M., Possnert, G., Brundin, L., & Frisén, J. (2019) · Nature · doi:10.1038/s41586-018-0842-3 · Cited by 376 · see citing works
Central nervous system regeneration is driven by microglia necroptosis and repopulation
Lloyd, A. F., Davies, C. L., Holloway, R. K., Labrak, Y., Ireland, G., Carradori, D., Dillenburg, A., Borger, E., Soong, D., Richardson, J. C., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0418-z · Cited by 316 · see citing works
Oligodendroglial myelination requires astrocyte-derived lipids
Camargo, N., Goudriaan, A., van Deijk, A.-L. F., Otte, W. M., Brouwers, J. F., Lodder, H., Gutmann, D. H., Nave, K.-A., Dijkhuizen, R. M., Mansvelder, H. D., et al. (2017) · PLOS Biology · doi:10.1371/journal.pbio.1002605 · Cited by 296 · see citing works
TREM2 regulates microglial cell activation in response to demyelination in vivo
Cantoni, C., Bollman, B., Licastro, D., Xie, M., Mikesell, R., Schmidt, R., Yuede, C. M., Galimberti, D., Olivecrona, G., Klein, R. S., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1388-1 · Cited by 296 · see citing works
Plemel, J. R., Stratton, J. A., Michaels, N. J., Rawji, K. S., Zhang, E., Sinha, S., Baaklini, C. S., Dong, Y., Ho, M., Thorburn, K., et al. (2020) · Science Advances · doi:10.1126/sciadv.aay6324 · Cited by 208 · see citing works
Murtie, J. C., Zhou, Y.-X., Le, T. Q., Vana, A. C., & Armstrong, R. C. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.12.006 · Cited by 157 · see citing works
Galectin-3 drives oligodendrocyte differentiation to control myelin integrity and function
Pasquini, L. A., Millet, V, Hoyos, H. C., Giannoni, J. P., Croci, D. O., Marder, M., Liu, F. T., Rabinovich, G. A., & Pasquini, J. M. (2011) · Cell Death & Differentiation · doi:10.1038/cdd.2011.40 · Cited by 152 · see citing works
Bogie, J. F. J., Grajchen, E., Wouters, E., Corrales, A. G., Dierckx, T., Vanherle, S., Mailleux, J., Gervois, P., Wolfs, E., Dehairs, J., et al. (2020) · Journal of Experimental Medicine · doi:10.1084/jem.20191660 · Cited by 151 · see citing works
Baxi, E. G., DeBruin, J., Tosi, D. M., Grishkan, I. V., Smith, M. D., Kirby, L. A., Strasburger, H. J., Fairchild, A. N., Calabresi, P. A., & Gocke, A. R. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.3817-14.2015 · Cited by 103 · see citing works
Starost, L., Lindner, M., Herold, M., Xu, Y. K. T., Drexler, H. C. A., Heß, K., Ehrlich, M., Ottoboni, L., Ruffini, F., Stehling, M., et al. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02217-8 · Cited by 79 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Microglia promote remyelination independent of their role in clearing myelin debris
Baaklini, C. S., Ho, M. F. S., Lange, T., Hammond, B. P., Panda, S. P., Zirngibl, M., Zia, S., Himmelsbach, K., Rana, H., Phillips, B., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113574 · Cited by 73 · see citing works
Saidha, S., Green, A. J., Leocani, L., Vidal-Jordana, A., Kenney, R. C., Bsteh, G., Outteryck, O., Thompson, A., Montalban, X., Coetzee, T., et al. (2025) · The Lancet Neurology · doi:10.1016/s1474-4422(25)00275-3 · Cited by 66 · see citing works
Distinct transcriptional changes distinguish efficient and poor remyelination in multiple sclerosis
Chen, J. Q. A., McNamara, N. B., Engelenburg, H. J., Jongejan, A., Wever, D. D., Hopman, K., van Rixel, E., Nijhuis, P. J. H., de Winter, F., Moerland, P. D., et al. (2025) · Brain · doi:10.1093/brain/awae414 · Cited by 17 · see citing works
BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis
Bergner, C. G., van der Meer, F., Franz, J., Vakrakou, A., Würfel, T., Nessler, S., Schäfer, L., Nau-Gietz, C., Winkler, A., Lagumersindez-Denis, N., et al. (2025) · Brain · doi:10.1093/brain/awae293 · Cited by 16 · see citing works
“For 64-67 This may also be true for the quiescent population of pre-differentiated BCAS1+ oligodendrocytes.”
Self-citationTGFβ signaling mediates microglial resilience to spatiotemporally restricted myelin degeneration
Zhu, K., Liu, Y., Min, J.-H., Joshua, V., Lin, J., Li, Y., Kreutzmann, J. C., Guo, Y., Xia, W., Mohammadi, E., et al. (2026) · Nature Neuroscience · doi:10.1038/s41593-025-02161-4 · Cited by 11 · see citing works
Inflammatory microglia correlate with impaired oligodendrocyte maturation in multiple sclerosis
Chen, J. Q. A., Wever, D. D., McNamara, N. B., Bourik, M., Smolders, J., Hamann, J., & Huitinga, I. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1522381 · Cited by 9 · see citing works
- Authors
- Franklin, R. J. M., & Simons, M.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- Corresponding author
- Franklin, Robin J.M.
- Simons, Mikael
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2022-11
- Volume
- 110
- Issue
- 21
- Pages
- 3549-3565
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W4304782981
- Cited by
- 184
- References
- 39
- Citations by year
- 2026: 44 · 2025: 55 · 2024: 59 · 2023: 25 · 2022: 1
- FWCI
- 5.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 366 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- DZNE Pub (submittedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion)
- Funders
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Multiple Sclerosis Society (MS50)
- European Research Council
- Deutsche Forschungsgemeinschaft (390857198, EXC2145, TRR 274, TRR128-2)
- Bundesministerium für Bildung und Forschung
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- remyelination, demyelination, multiple sclerosis, neuroinflammation, innate immunity, saltatory conduction, progressive multiple sclerosis
- MeSH terms
- Remyelination, Humans, Inflammation, Multiple Sclerosis, Myelin Sheath, Oligodendroglia
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
