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Inefficient clearance of myelin debris by microglia impairs remyelinating processes
Open accessAbstract
An imbalance between remyelinating and demyelinating rates underlies degenerative processes in demyelinating diseases such as multiple sclerosis. An optimal therapeutic strategy would be to stimulate remyelination while limiting demyelination. Although accumulation of myelin debris impairs remyelination, the mechanisms regulating the clearance of such debris by mononuclear phagocytic cells are poorly understood. We demonstrate that after cuprizone intoxication, CCR2-dependent infiltration of mouse bone marrow-derived cells is abundant in demyelinating areas, but that these cells do not impact demyelination. However, in CX3CR1-deficient mice, the clearance of myelin debris by microglia was blocked greatly, affecting the integrity of the axon and myelin sheaths and thus preventing proper remyelination. These results highlight the crucial role played by CX3CR1 in myelin removal and show that there can be no efficient remyelination after a primary demyelinating insult if myelin clearance by microglia is impaired.
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“Mounting evidence suggests that microglia, which are the professional phagocytes of the CNS, are critically involved in ensuring the proper containment and removal of neurotoxic material in neurodegenerative disease pathogenesis (Condello et al., 2015; Hickman et al., 2018; Lampron et al., 2015).”
From SYK coordinates neuroprotective microglial responses in neurodegenerative disease (2022) · cites this paper as Lampron et al., 2015
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“Cessation of cuprizone leads to subsequent remyelination, and clearance of myelin debris is believed to be crucial for remyelination and recovery [5,6].”
From Multifaceted response of microglia in the cuprizone model of demyelination (2026) · cites this paper as [5]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Microglia also clear myelin debris, and secrete trophic factors to promote oligodendrocyte growth and survival [5,11,12].”
From Multifaceted response of microglia in the cuprizone model of demyelination (2026) · cites this paper as [5]
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“indicating that microglial clearance of myelin debris continues following cuprizone withdrawal, as reported in previous studies [3,5].”
From Multifaceted response of microglia in the cuprizone model of demyelination (2026) · cites this paper as [5]
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“Accumulation of debris within lesions has been demonstrated to inhibit oligodendrocyte recruitment and differentiation (18, 41, 44) and, thus, delay recovery/remyelination.”
From Microglia depletion exacerbates demyelination and impairs remyelination in a neurotropic coronavirus infection (2020) · cites this paper as [44]
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“Long-term demyelination occurs post-SCI, with lipid-containing myelin debris being absorbed and processed by inflammatory cells, including microglia—a process crucial for paving the way for regenerative reactions and inflammation resolution [9–11].”
From miR-223 accelerates lipid droplets clearance in microglia following spinal cord injury by upregulating ABCA1 (2024) · cites this paper as [10]
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“Efficient myelin debris removal and clearance by phagocytic cells are critical to eliminate inhibitory signals interfering with OPC activation, recruitment to the site of demyelination and/or differentiation into myelinating mature OLs [14, 26, 27].”
From TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis (2020) · cites this paper as [27]
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“Recruited cell populations included monocytes and lymphocytes.”
From Cuprizone‐induced demyelination triggers a CD8‐pronounced T cell recruitment (2021) · cites this paper as Lampron et al., 2015
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“In line with our observation, Lampron and colleagues demonstrated a significant infiltration of transplanted GFP-expressing bone-marrow cells into the CNS, with a peak of infiltration at weeks 4 and 5 of intoxication (Lampron et al., 2015).”
From Cuprizone‐induced demyelination triggers a CD8‐pronounced T cell recruitment (2021) · cites this paper as Lampron et al., 2015
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“When CCR2 -/-instead of CCR2 +/+ bone-marrow cells were transplanted, infiltration into the CNS was almost completely blocked without affecting the extent of cuprizoneinduced demyelination.”
From Cuprizone‐induced demyelination triggers a CD8‐pronounced T cell recruitment (2021) · cites this paper as Lampron et al., 2015
In the citing paper
“Activated microglia within the demyelinating areas of CPZ lesions express various cytokines, chemokines and growth factors (21, 22), and inefficient clearance of myelin debris by microglia impairs remyelinating processes in the CPZ model (23).”
From Absence of miRNA-146a Differentially Alters Microglia Function and Proteome (2020) · cites this paper as [23]
In the citing paper
“Thus, removal of myelin debris by microglia is important for oligodendrocyte proliferation and stimulation of remyelination, which can be achieved with a neuroprotective microglial phenotype (Lampron et al. 2015).”
From MiR-124 and MiR-155 as Therapeutic Targets in Microglia-Mediated Inflammation in Multiple Sclerosis (2025) · cites this paper as Lampron et al. 2015
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Metadata
- Authors
- 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.
- Affiliations
- Université Laval (CA)
- University of Calgary (CA)
- Corresponding author
- Rivest, Serge
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2015-03-16
- Volume
- 212
- Issue
- 4
- Pages
- 481-495
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC4387282
- OpenAlex
- W2096423240
- Cited by
- 595
- References
- 77
- Citations by year
- 2026: 45 · 2025: 42 · 2024: 46 · 2023: 78 · 2022: 86 · 2021: 55 · 2020: 60 · 2019: 61 · 2018: 44 · 2017: 38 · 2016: 29 · 2015: 11
- FWCI
- 32.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- remyelination, myelin debris clearance, microglia, CX3CR1, CCR2, demyelination, multiple sclerosis, cuprizone, bone marrow-derived cells, axon integrity
- MeSH terms
- CX3C Chemokine Receptor 1, Animals, Axons, Bone Marrow Cells, Demyelinating Diseases, Myelin Sheath, Phagocytes, Microglia, Mice, Knockout, Receptors, Chemokine, Mice, Receptors, CCR2
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