Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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TREM2 regulates microglial cell activation in response to demyelination in vivo

ABSTRACT: 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),

ORGANISM(S): Mus musculus

SUBMITTER: Danilo Licastro

PROVIDER: E-GEOD-70475 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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TREM2 regulates microglial cell activation in response to demyelination in vivo.

Cantoni Claudia C Bollman Bryan B Licastro Danilo D Xie Mingqiang M Mikesell Robert R Schmidt Robert R Yuede Carla M CM Galimberti Daniela D Olivecrona Gunilla G Klein Robyn S RS Cross Anne H AH Otero Karel K Piccio Laura L

Acta neuropathologica 20150129 3

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 ...[more]

PMID: 25631124

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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.

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TREM2 regulates microglial cell activation in response to demyelination in vivo

Publications

TREM2 regulates microglial cell activation in response to demyelination in vivo.

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