Loss of ‘homeostatic’ microglia and patterns of their activation in active multiple sclerosis
Open accessAbstract
Microglia and macrophages accumulate at the sites of active demyelination and neurodegeneration in the multiple sclerosis brain and are thought to play a central role in the disease process. We used recently described markers to characterize the origin and functional states of microglia/macrophages in acute, relapsing and progressive multiple sclerosis. We found microglia activation in normal white matter of controls and that the degree of activation increased with age. This microglia activation was more pronounced in the normal-appearing white matter of patients in comparison to controls and increased with disease duration. In contrast to controls, the normal-appearing white matter of patients with multiple sclerosis showed a significant reduction of P2RY12, a marker expressed in homeostatic microglia in rodents, which was completely lost in active and slowly expanding lesions. Early stages of demyelination and neurodegeneration in active lesions contained microglia with a pro-inflammatory phenotype, which expressed molecules involved in phagocytosis, oxidative injury, antigen presentation and T cell co-stimulation. In later stages, the microglia and macrophages in active lesions changed to a phenotype that was intermediate between pro- and anti-inflammatory activation. In inactive lesions, the density of microglia/macrophages was significantly reduced and microglia in part converted to a P2RY12+ phenotype. Analysis of TMEM119, which is expressed on microglia but not on recruited macrophages, demonstrated that on average 45% of the macrophage-like cells in active lesions were derived from the resident microglia pool. Our study demonstrates the loss of the homeostatic microglial signature in active multiple sclerosis with restoration associated with disease inactivity.
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Microglia in active MS lesions lack Tmem119.
“Similarly, microglia in active MS lesions lack Tmem119 (Satoh et al., 2016; Zrzavy et al., 2017).”
From Activated microglia drive demyelination via <scp>CSF1R</scp> signaling (2021) · cites this paper as Zrzavy et al., 2017
The Results section (‘The contribution of resident microglia versus recruited macrophages in multiple sclerosis brain’) reports that, in early active lesions, an average of 43% of Iba1-positive cells were TMEM119-positive. TMEM119-positive cells became less numerous as active lesions advanced, but the paper does not say that microglia in active lesions lack TMEM119. (LLM, conf=0.91)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredMicroglial cells within active white matter lesions are characterized by the absence of homeostatic markers such as P2RY12 and an upregulation of CXCR4, indicating a shift to a disease-associated state.
“Microglial cells within active white matter lesions are characterized by the absence of homeostatic markers such as P2RY12 and an upregulation of CXCR4, indicating a shift to a disease-associated state (31, 41, 42).”
From The role of microglia in multiple sclerosis: implications for treatment with Bruton’s tyrosine kinase inhibitors (2025) · cites this paper as [41]
The Results section reports that most microglia-like cells in classical active lesions are activated and lack P2RY12; the Discussion describes this as loss of the homeostatic phenotype. The paper does not report CXCR4 upregulation in these cells, so that specific part of the claim is unsupported by this source. Page numbers were not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTMEM119 has been shown to be downregulated in active MS lesions and other inflammatory conditions of the brain.
“TMEM119 is one of the main homeostatic microglia markers that is not expressed on monocyte-derived macrophages and has been shown to be downregulated in active MS lesions and other inflammatory conditions of the brain47–49.”
From CHIT1 at diagnosis predicts faster disability progression and reflects early microglial activation in multiple sclerosis (2024) · cites this paper as [47]
The Results report that TMEM119 is present in only a subset of cells in early active MS lesions and that few TMEM119-positive cells remain in active lesion centres (Figures 1 and 4; page unavailable). The paper does not establish TMEM119 downregulation in other inflammatory brain conditions; it also distinguishes TMEM119 from P2RY12, the marker it describes as homeostatic. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe phenotype of microglia observed in HDLS is similar to that found in an SOD1 ALS mouse model and in multiple sclerosis patients, in which the molecules associated with the homeostatic microglial phenotype (e.g., P2RY12, CSF-1R) are down-regulated and inflammatory markers are up-regulated.
“Interestingly, the phenotype of microglia we observed in HDLS is similar to that found in an SOD1 ALS mouse model and in multiple sclerosis patients, in which the molecules associated with the homeostatic microglial phenotype (e.g., P2RY12, CSF-1R) are down-regulated and inflammatory markers are up-regulated [24, 57].”
From Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy (2020) · cites this paper as [57]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredP2RY12+ cells expressing TSPO are substantially reduced in active lesions.
“As reported previously (Zrzavy et al., 2017), P2RY12+ cells expressing TSPO were substantially reduced in active lesions (Fig. 2E–H).”
From A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis (2019) · cites this paper as Zrzavy et al., 2017
The Results (Figure 4 caption; page unavailable) report that P2RY12 expression is massively reduced in TMEM119+ cells in initial lesions and falls further in early active lesions. The cited paper does not establish that the reduced P2RY12+ cells express TSPO; its reported co-staining is for P2RY12 and TMEM119. (LLM, conf=0.88)
Experimental — accuracy not yet measured
In contrast to the pattern of TSPO expression in rodent models, TSPO may not be so specifically associated with pro-inflammatory microglia in multiple sclerosis.
“Thus, in contrast to the pattern of TSPO expression in rodent models, it may not be so specifically associated with pro-inflammatory microglia in multiple sclerosis (Zrzavy et al., 2017).”
From A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis (2019) · cites this paper as Zrzavy et al., 2017
The Discussion (page unavailable) reports that human microglia show background pro-inflammatory activation unlike microglia in normal rodent brain, and calls for PET markers that distinguish microglial functional states. But the paper does not examine TSPO or establish whether its expression is less specifically associated with pro-inflammatory microglia in multiple sclerosis. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMost phagocytes initially present in active MS lesions are microglia, and with lesion maturation, more macrophages will infiltrate from the blood.
“Indeed, most phagocytes initially present in active MS lesions are microglia, and with lesion maturation, more macrophages will infiltrate from the blood47.”
From CHIT1 at diagnosis predicts faster disability progression and reflects early microglial activation in multiple sclerosis (2024) · cites this paper as [47]
TMEM119 is one of the main homeostatic microglia markers that is not expressed on monocyte-derived macrophages.
“TMEM119 is one of the main homeostatic microglia markers that is not expressed on monocyte-derived macrophages and has been shown to be downregulated in active MS lesions and other inflammatory conditions of the brain47–49.”
From CHIT1 at diagnosis predicts faster disability progression and reflects early microglial activation in multiple sclerosis (2024) · cites this paper as [47]
The loss of homeostatic microglial proteins is visible in immunofluorescence double-staining of IBA1 and TMEM119 in terminally sick mice and mock-infected healthy control brains, and shows reciprocal regulation of both proteins in prion disease.
“The loss of homeostatic microglial proteins is visible in immunofluorescence double-staining of IBA1 and TMEM119 in terminally sick mice and mock-infected healthy control brains, and shows the reciprocal regulation of both proteins in prion disease (Figure 5A) [55,73,88,89,90,91].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [90]
Human Tmem119 expression is maintained by resident microglia in MS lesions and is not expressed by infiltrating immune cells.
“since its expression is maintained by resident human microglia in MS lesions and is not expressed by infiltrating immune cells (Zrzavy et al., 2017).”
From Complex cell-state changes revealed by single cell RNA sequencing of 76,149 microglia throughout the mouse lifespan and in the injured brain (2018) · cites this paper as Zrzavy et al., 2017
P2RY12 and TMEM119 are also expressed in human microglia.
“Several of these microglial genes were also observed in human microglia, including P2RY12 and TMEM119 (REFs25,33–36).”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [36]
In human multiple sclerosis, microglia lose P2RY12 expression and adopt a pro-inflammatory phenotype with phagocytic markers, antigen presentation markers and reactive oxygen species production proteins.
“In human MS, microglia lose the expression of the P2RY12 homeostatic microglial marker and adopt a pro-inflammatory phenotype that includes the expression of phagocytic-related markers (macrosialin (also known as CD68)), antigen presentation markers (MHC class I and II molecules and T lymphocyte activation antigen CD86) and proteins involved in the production of reactive oxygen species (cytochrome”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [36]
TMEM119 appears to exhibit stable expression even in response to a variety of inflammatory conditions.
“and appears to exhibit stable expression even in response to a variety of inflammatory conditions (9, 96).”
From The Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease (2019) · cites this paper as [96]
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“Downregulation of Tmem119 is shared by all models of demyelination used in this study (CUP and LPC) and is a feature of disease-associated microglia (Deczkowska et al., 2018).”
BackgroundInfluentialMicroglial inflammation and phagocytosis in Alzheimer's disease: Potential therapeutic targets
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The Role of Microglia in Modulating Neuroinflammation after Spinal Cord Injury
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Microglia: Brain cells on the move
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Pro‐inflammatory activation of microglia in the brain of patients with sepsis
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Natural Products as a Potential Modulator of Microglial Polarization in Neurodegenerative Diseases
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- Authors
- Zrzavy, T., Hametner, S., Wimmer, I., Butovsky, O., Weiner, H. L., & Lassmann, H.
- Affiliations
- Medical University of Vienna (AT)
- Brigham and Women's Hospital (US)
- Corresponding author
- Lassmann, Hans
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-05-24
- Volume
- 140
- Issue
- 7
- Pages
- 1900-1913
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC6057548
- OpenAlex
- W2620266814
- Cited by
- 684
- References
- 68
- Citations by year
- 2026: 62 · 2025: 65 · 2024: 78 · 2023: 87 · 2022: 92 · 2021: 116 · 2020: 71 · 2019: 60 · 2018: 43 · 2017: 10
- FWCI
- 39.52
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- NIH (R01NS088137)
- National Multiple Sclerosis Society (5092A1)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- multiple sclerosis, microglia, macrophages, homeostatic microglia, microglial activation, P2Y12 receptor, TMEM119, normal-appearing white matter, demyelination, neurodegeneration, lesion activity, disease duration, pro-inflammatory phenotype, anti-inflammatory phenotype, phagocytosis, oxidative damage, antigen presentation, T cell costimulation, microglial origin
- MeSH terms
- Adult, Aged, Aged, 80 and over, Aging, Demyelinating Diseases, Female, Homeostasis, Humans, Macrophage Activation, Male, Membrane Proteins, Middle Aged, Multiple Sclerosis, Nerve Degeneration, Case-Control Studies, Microglia, Receptors, Purinergic P2Y12, White Matter
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