Identification of a microglia phenotype supportive of remyelination
Open accessAbstract
In multiple sclerosis, endogenous oligodendrocyte precursor cells (OPCs) attempt to remyelinate areas of myelin damage. During disease progression, however, these attempts fail. It has been suggested that modulating the inflammatory environment of the lesion might provide a promising therapeutic approach to promote endogenous remyelination. Microglia are known to play a central role in neuroinflammatory processes. To investigate the microglia phenotype that supports remyelination, we performed genome‐wide gene expression analysis of microglia from the corpus callosum during demyelination and remyelination in the mouse cuprizone model, in which remyelination spontaneously occurs after an episode of toxin‐induced primary demyelination. We provide evidence for the existence of a microglia phenotype that supports remyelination already at the onset of demyelination and persists throughout the remyelination process. Our data show that microglia are involved in the phagocytosis of myelin debris and apoptotic cells during demyelination. Furthermore, they express a cytokine and chemokine repertoire enabling them to activate and recruit endogenous OPCs to the lesion site and deliver trophic support during remyelination. This study not only provides a detailed transcriptomic analysis of the remyelination‐supportive microglia phenotype but also reinforces the notion that the primary function of microglia is the maintenance of tissue homeostasis and the support of regeneration already at the earliest stages in the development of demyelinating lesions. © 2011 Wiley Periodicals, Inc.
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Microglia at both 14 and 21 dpi up-regulated genes critical for the uptake and degradation of cellular and myelin debris, such as Apoe, Clec7a, and Axl.
“Furthermore, microglia at both 14 and 21 dpi up-regulated genes critical for the uptake and degradation of cellular and myelin debris, such as Apoe, Clec7a, and Axl (41–43).”
From Microglia depletion exacerbates demyelination and impairs remyelination in a neurotropic coronavirus infection (2020) · cites this paper as [42]
The Microglia Phenotype section (page unavailable) reports Clec7a upregulation during demyelination and remyelination and identifies Apoe with salvage of myelin constituents. The gene-expression confirmation section also reports Apoe upregulation in microglia. The paper uses weeks of demyelination and remyelination rather than 14 and 21 dpi, and the retrieved passages do not establish Axl upregulation at those time points. (LLM, conf=0.87)
Experimental — accuracy not yet measuredA switch from M1- to M2-associated gene expression has been reported during cutaneous wound healing but has not been observed in studies of immune-mediated and toxin (cuprizone)-induced demyelination.
“A switch from M1- to M2-associated gene expression has been reported during cutaneous wound healing8 but has not been observed in studies of immune-mediated36 and toxin (cuprizone)-induced demyelination37.”
From M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination (2013) · cites this paper as [37]
CD247 (B7-H1) was up-regulated on microglia throughout de- and remyelination.
“Olah and colleges have shown that CD247 (B7-H1), a known immune inhibitory molecule (Magnus et al., 2005; Ortler et al., 2008) was up-regulated on microglia throughout de- and remyelination (Olah et al., 2012).”
From Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned (2014) · cites this paper as Olah et al., 2012
In the cuprizone model, microglia seem not to be assigned to a certain phenotype characteristic either for de- or remyelination, since most regulated genes showed unidirectional up-regulation or down-regulation throughout de- and remyelination.
“In addition, in this model microglia seem not to be assigned to a certain phenotype characteristic either for de- or remyelination since most of the genes that were regulated showed an unidirectional up-regulation or down-regulation throughout the de- and remyelination processes (Olah et al., 2012)”
From Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned (2014) · cites this paper as Olah et al., 2012
Regional and age-related differences in microglial density, morphology, gene, and protein expression have previously been described for both animals and humans.
“Regional and age-related differences in microglial density, morphology, gene, and protein expression have previously been described for both animals and humans5,6,9,60,61.”
From Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies (2022) · cites this paper as [61]
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References 74 · Cited by 358
Research works printed but not linked: 1
- Li WW, Setzu A, Zhao C, Franklin RJ. 2005. Minocycline-mediated inhibition of microglia activation impairs oligodendrocyte progenitor GLIA 10981136, 2012, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/glia.21266, Wiley Online Library on [14/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License cell responses and remyelination in a non-immune model of demye- lination. J Neuroimmunol 158:58-66.
- Authors
- Olah, M., Amor, S., Brouwer, N., Vinet, J., Eggen, B., Biber, K., & Boddeke, H. W. G. M.
- Affiliations
- University Medical Center Groningen (NL)
- Queen Mary University of London (GB)
- Corresponding author
- Boddeke, Hendrikus W. G. M.
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2011-11-09
- Volume
- 60
- Issue
- 2
- Pages
- 306-321
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- OpenAlex
- W2053646585
- Cited by
- 358
- References
- 74
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 26 · 2023: 12 · 2022: 29 · 2021: 31 · 2020: 31 · 2019: 31 · 2018: 21 · 2017: 25 · 2016: 20 · 2015: 36 · 2014: 27 · 2013: 31 · 2012: 18
- FWCI
- 17.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Glia (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Pure Amsterdam UMC (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- microglia phenotype, remyelination, multiple sclerosis, oligodendrocyte precursor cells, demyelination, cuprizone model, myelin phagocytosis, efferocytosis, cytokines and chemokines, microglial transcriptome, tissue homeostasis, corpus callosum
- MeSH terms
- Animals, Demyelinating Diseases, Disease Models, Animal, Male, Mice, Inbred C57BL, Myelin Sheath, Nerve Fibers, Myelinated, Nerve Regeneration, Phenotype, Microglia, Mice
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