Trem2 deficiency does not alter virus control but impairs phagocytic activity during neurotropic coronavirus induced demyelination
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PROVIDER: PRJNA852802 | ENA |
REPOSITORIES: ENA
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Project description:Triggering receptor expressed on myeloid cells 2 (TREM2) plays a protective role in neurodegenerative diseases, including Alzheimer’s and demyelinating diseases. However, Trem2 functions can exacerbate tissue damage during viral respiratory or liver infections. We therefore investigated the role of TREM2 in a viral encephalomyelitis model associated with prominent Th1 responses and demyelination. To address our hypothesis, Wild type (WT) and Trem2-/- mice were infected with a sublethal glia tropic murine coronavirus (MHV-JHM) was intracranially. Disease progression and survival were monitored daily. Immune response and demyelination in the spinal cord (SC) were determined by flow cytometry and immunofluorescences analysis. Expression of Inflammatory cytokines was measured with RT-PCR. Differential gene expression in sorted SC-derived microglia and infiltrated bone marrow-derived macrophages (BMDM) were determined by Nanostring, nCounter system, which directly captures and counts individual mRNA transcripts thereby omitting cDNA-based amplification. Upon infection, BMDM highly upregulated Trem2 mRNA compared to microglia, which showed a delayed increase coincident with demyelination. Although TREM2 deficiency did not alter disease onset and severity, it impaired clinical recovery during establishment of viral persistence associated with demyelination. Disease progression in Trem2-/- mice was not associated with altered virus control, leukocyte recruitment or overall inflammatory responses in the SC. However, there was a significant increase in degenerated myelin not associated with the myeloid markers IBA1 and/or CD68 in the lesions. Gene expression profiles of SC-derived microglia and BMDM using the Nanostring platform revealed that TREM2 deficiency resulted in the failure to upregulate genes associated with phagocytosis, including LPL and CD36. Overall our data using a virus infection model show that TREM2 deficiency does not affect viral control or T cell immunity but leads to impaired expression of select phagocytic pathway factors, ultimately resulting in failure to remove damaged myelin in demyelinated lesions. The results support that TREM2 dependent removal of damaged myelin is independent of the initial insult or the inflammatory milieu, but rather regulated by sensing a dysregulated lipid environment.
2022-11-09 | GSE206942 | GEO
Project description:Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage. Two STAGE (6weeks 12 weeks),
2015-07-06 | E-GEOD-70475 | biostudies-arrayexpress
Project description:We examined the role of TREM2 on microglia responses to demyelination Microglia were FACS-purified from WT or Trem2-/- mice fed with 0.2% cuprizone diet.
2015-04-22 | E-GEOD-66926 | biostudies-arrayexpress
Project description:TREM2 is a microglial-specific gene implicated in late-onset Alzheimer's Disease (AD). Recent studies have identified that Trem2-deficient mice exhibit transcriptional changes in microglial gene expression that minimize the upregulation of lipid metabolism and lysosomal genes in AD disease models. We find that chronic phagocytic challenge from demyelination generates similiarly attenuated expression of lysosomal and lipid metabolism genes in microglia isolated from Trem2 knockout mouse brain.
2019-12-21 | GSE124266 | GEO
Project description:TREM2 is a microglial-specific gene implicated in late-onset Alzheimer's Disease (AD). Recent studies have identified that Trem2-deficient mice exhibit transcriptional changes in microglial gene expression that minimize the upregulation of lipid metabolism and lysosomal genes in AD disease models. We find that chronic phagocytic challenge from demyelination generates similiarly attenuated expression of lysosomal and lipid metabolism genes in microglia isolated from Trem2 knockout mouse brain.
2019-12-21 | GSE130626 | GEO
Project description:Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage.
2015-07-06 | GSE70475 | GEO
Project description:We examined the role of TREM2 on microglia responses to demyelination
2015-04-22 | GSE66926 | GEO
Project description:TREM-2 has been described to be a phagocytic receptor. We assessed the influence of TREM-2 on gene expression in alveolar macrophages (AM) In this data-set we characterised the differences in basal gene expression using affymetrix mouse 1.0 ST arrays between WT and TREM2-/- AM and observed TREM2 -/- AM to exhibt higher expression of opsonins 4 samples were analysed in biological duplicate (2 x WT and 2 x TREM2-/-)
2015-01-01 | E-GEOD-51378 | biostudies-arrayexpress
Project description:Triggering receptor expressed on myeloid cell 2 (TREM2) is linked to neurodegenerative disease risk. However, the function of TREM in neurodegeneration is still unclear. Here we investigated the role of microglial TREM2 in TAR-DNA binding protein 43 kDa (TDP-43)-related neurodegeneration using viral-mediated and transgenic mouse models. We found that TREM2 deficiency impaired phagocytic clearance of pathological TDP-43 by microglia, and enhanced neuronal damage and motor impairments. Mass cytometry analysis revealed that hTDP-43 induced a TREM2-dependent subpopulation of microglia with high CD11c expression and phagocytic ability. Using mass spectrometry and surface plasmon resonance analysis, we further demonstrated an interaction between TDP-43 and TREM2 in vitro and in vivo as well as in ALS patient tissues. We computationally identified the region within hTDP-43 that interacts with TREM2. Our data highlights that TDP-43 is a possible ligand for microglial TREM2 and that this interaction mediates neuroprotection effects of microglia in TDP-43-related neurodegeneration.
2022-08-12 | PXD029429 | Pride
Project description:TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge
| PRJNA540829 | ENA