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Activation Status of Human Microglia Is Dependent on Lesion Formation Stage and Remyelination in Multiple Sclerosis
Open accessAbstract
Similar to macrophages, microglia adopt diverse activation states and contribute to repair and tissue damage in multiple sclerosis. Using reverse transcription-quantitative polymerase chain reaction and immunohistochemistry, we show that in vitro M1-polarized (proinflammatory) human adult microglia express the distinctive markers CD74, CD40, CD86, and CCR7, whereas M2 (anti-inflammatory) microglia express mannose receptor and the anti-inflammatory cytokine CCL22. The expression of these markers was assessed in clusters of activated microglia in normal-appearing white matter (preactive lesions) and areas of remyelination, representing reparative multiple sclerosis lesions. We show that activated microglia in preactive and remyelinating lesions express CD74, CD40, CD86, and the M2 markers CCL22 and CD209, but not mannose receptor. To examine whether this intermediate microglia profile is static or dynamic and thus susceptible to changes in the microenvironment, we polarized microglia into M1 or M2 phenotype in vitro and then subsequently treated them with the opposing polarization regimen. These studies revealed that expression of CD40, CXCL10, and mannose receptor is dynamic and that microglia, like macrophages, can switch between M1 and M2 phenotypic profiles. Taken together, our data define the differential activation states of microglia during lesion development in multiple sclerosis-affected CNS tissues and underscore the plasticity of human adult microglia in vitro.
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“Here, we show that the increased TSPO expression in multiple sclerosis lesions primarily represents an intermediate activation state in which cells expressed both CD40 and CD206 (Vogel et al., 2013; Peferoen et al., 2015); microglia solely expressing the pro-inflammatory marker CD40 or the anti-inflammatory marker mannose receptor CD206 were sparsely represented.”
From A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis (2019) · cites this paper as Peferoen et al., 2015
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“Additionally, microglia/macrophages in multiple sclerosis lesions adopt an intermediate phenotype, and the classical M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotypes probably represent extreme states only found in vitro (Peferoen et al., 2015).”
From A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis (2019) · cites this paper as Peferoen et al., 2015
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“Here, we show that the increased TSPO expression in multiple sclerosis lesions primarily represents an intermediate activation state in which cells expressed both CD40 and CD206 (Vogel et al., 2013; Peferoen et al., 2015); microglia solely expressing the pro-inflammatory marker CD40 or the anti-inflammatory marker mannose receptor CD206 were sparsely represented.”
From A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis (2019) · cites this paper as Peferoen et al., 2015
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Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages
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Amplification efficiency: linking baseline and bias in the analysis of quantitative PCR data
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Microglial physiology: unique stimuli, specialized responses
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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 1,777
Microglia in neurodegenerative disease
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Lan, X., Han, X., Li, Q., Yang, Q.-W., & Wang, J. (2017) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.69 · Cited by 915
Loss of ‘homeostatic’ microglia and patterns of their activation in active multiple sclerosis
Zrzavy, T., Hametner, S., Wimmer, I., Butovsky, O., Weiner, H. L., & Lassmann, H. (2017) · Brain · doi:10.1093/brain/awx113 · Cited by 684
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Metadata
- Authors
- Peferoen, L. A. N., Vogel, D. Y. S., Ummenthum, K., Breur, M., Heijnen, P. D. A. M., Gerritsen, W. H., Peferoen-Baert, R. M. B., van der Valk, P., Dijkstra, C. D., & Amor, S.
- Affiliations
- Queen Mary University of London (GB)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Corresponding author
- Amor, Sandra
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-01
- Volume
- 74
- Issue
- 1
- Pages
- 48-63
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- OpenAlex
- W2079198405
- Cited by
- 178
- References
- 66
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 10 · 2023: 11 · 2022: 19 · 2021: 11 · 2020: 18 · 2019: 24 · 2018: 13 · 2017: 17 · 2016: 26 · 2015: 15
- FWCI
- 14.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- 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
- microglial activation, multiple sclerosis, remyelination, macrophage polarization, microglial plasticity, CD40, CD74, CCL22, CD206, CD86, CXCL10, normal-appearing white matter, lesion progression, microglial markers
- MeSH terms
- Aged, Aged, 80 and over, Histocompatibility Antigens Class II, Brain, Cell Differentiation, Cells, Cultured, Female, Flow Cytometry, Humans, Macrophages, Male, Middle Aged, Multiple Sclerosis, RNA, Messenger, Antigens, CD, Cytokines, Microglia, Statistics, Nonparametric, Myelin Proteolipid Protein, Transcriptome
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