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Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions

ABSTRACT: Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions

PROVIDER: PRJNA663188 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12630900_1.fastq.gz	Fastqsanger.gz
	SRR12630900_2.fastq.gz	Fastqsanger.gz
	SRR12630901_1.fastq.gz	Fastqsanger.gz
	SRR12630901_2.fastq.gz	Fastqsanger.gz
	SRR12630902_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions

Project description:The purpose of this project was to investigate whole genome expression in primary microglia cultured from homozygous Trem2 R47H knock-in mice versus wild type littermates under basal conditions and in response to IL-4 treatment. The primary phenotype of microglia from Trem2 R47H knock-in mice was decreased expression levels of Trem2. IL-4 induced the expression of an anti-inflammatory programme of genes in microglia, which was attenuated when Trem2 expression was decreased.

2020-09-30 | GSE157891 | GEO

Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions.

Project description:Genome-wide association studies have reported that, amongst other microglial genes, variants in TREM2 can profoundly increase the incidence of developing Alzheimer's disease (AD). We have investigated the role of TREM2 in primary microglial cultures from wild type mice by using siRNA to decrease Trem2 expression, and in parallel from knock-in mice heterozygous or homozygous for the Trem2 R47H AD risk variant. The prevailing phenotype of Trem2 R47H knock-in mice was decreased expression levels of Trem2 in microglia, which resulted in decreased density of microglia in the hippocampus. Overall, primary microglia with reduced Trem2 expression, either by siRNA or from the R47H knock-in mice, displayed a similar phenotype. Comparison of the effects of decreased Trem2 expression under conditions of lipopolysaccharide (LPS) pro-inflammatory or IL-4 anti-inflammatory stimulation revealed the importance of Trem2 in driving a number of the genes up-regulated in the anti-inflammatory phenotype. RNA-seq analysis showed that IL-4 induced the expression of a program of genes including Arg1 and Ap1b1 in microglia, which showed an attenuated response to IL-4 when Trem2 expression was decreased. Genes showing a similar expression profile to Arg1 were enriched for STAT6 transcription factor recognition elements in their promoter, and Trem2 knockdown decreased levels of STAT6. LPS-induced pro-inflammatory stimulation suppressed Trem2 expression, thus preventing TREM2's anti-inflammatory drive. Given that anti-inflammatory signaling is associated with tissue repair, understanding the signaling mechanisms downstream of Trem2 in coordinating the pro- and anti-inflammatory balance of microglia, particularly mediating effects of the IL-4-regulated anti-inflammatory pathway, has important implications for fighting neurodegenerative disease.

| S-EPMC7689298 | biostudies-literature

Effects of ATV:TREM2 and pro-inflammatory stimuli on transcriptome of WT iPSC-derived microglia

Project description:ATV:TREM2 induces robust G2M checkpoint geneset and is differentiated from pro-inflammatory or mitogenic signatures induced by LPS, TGFb, and IFNg

2022-11-23 | GSE199154 | GEO

iPSC-derived microglia carrying the TREM2 R47H/+ mutation are pro-inflammatory and promote synapse loss.

Project description:Genetic findings have highlighted key roles for microglia in the pathology of neurodegenerative conditions such as Alzheimer’s disease (AD). A number of mutations in the microglial protein TREM2 (triggering receptor expressed on myeloid cells 2) have been associated with increased risk for developing Alzheimer’s disease (AD), most notably the R47H/+ substitution. We employed gene editing and stem cell models to gain insight into the effects of the TREM2 R47H/+ mutation on human iPSC-derived microglia. We found transcriptional changes affecting numerous cellular processes, with R47H/+ cells exhibiting a pro-inflammatory gene expression signature. TREM2 R47H/+ also caused impairments in microglial movement and the uptake of multiple substrates, as well as rendering microglia hyper-responsive to inflammatory stimuli. We developed an in vitro laser-induced injury model in neuron-microglia co-cultures, finding an impaired injury response by TREM2 R47H/+ microglia. Furthermore, mouse brains transplanted with TREM2 R47H/+ microglia exhibited reduced synaptic density, with upregulation of multiple complement cascade components in TREM2 R47H/+ microglia suggesting inappropriate synaptic pruning as one potential mechanism. These findings identify a number of potentially detrimental effects of the TREM2 R47H/+ mutation on microglial gene expression and function likely to underlie its association with AD.

2024-03-06 | GSE241858 | GEO

iPSC-derived microglia carrying the TREM2 R47H/+ mutation are pro-inflammatory and promote synapse loss.

Project description:iPSC-derived microglia carrying the TREM2 R47H/+ mutation are pro-inflammatory and promote synapse loss.

| PRJNA1010350 | ENA

Effects of ATV:TREM2 and pro-inflammatory stimuli on transcriptome of WT iPSC-derived microglia

Project description:Effects of ATV:TREM2 and pro-inflammatory stimuli on transcriptome of WT iPSC-derived microglia

| PRJNA818664 | ENA

Expression data from WT and TREM2 deficient microglia in a mouse model of Alzheimer's disease

Project description:We examined the role of TREM2 on microglia responses to amyloid-beta deposition in a mouse model of Alzheimer's disease Microglia were FACS-purified from 8.5 month old WT, Trem2-/-, 5XFAD, and Trem2-/- 5XFAD mice

2015-03-13 | E-GEOD-65067 | biostudies-arrayexpress

Expression data from WT and TREM2 deficient microglia in response to cuprizone mediated demyelination

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

TREM2 regulates microglial cell activation in response to demyelination in vivo

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

Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's Disease model

Project description:TREM2 is a receptor for lipids expressed in microglia. The R47H variant of human TREM2 impairs ligand binding and increases Alzheimer’s Disease (AD) risk. In mouse models of amyloid b (Ab) accumulation, defective TREM2 function affects microglial response to Ab plaques exacerbating tissue damage, whereas TREM2 overexpression attenuates pathology. Thus, AD may benefit from TREM2 activation. Here, we examined the impact of an anti-human TREM2 agonistic mAb, AL002c, in a mouse AD model expressing either the common variant (CV) or the R47H variant of TREM2. Single cell RNA-seq of microglia after acute systemic administration of AL002c showed induction of proliferation in both CV- and R47H-transgenic mice. Prolonged administration of AL002c reduced filamentous plaques and neurite dystrophy, impacted behavior and tempered glial inflammatory response. We further showed that a variant of AL002c has been given safely in a first-in-human phase I clinical trial and engages TREM2 based on CSF biomarkers. We conclude that AL002c is a promising candidate for AD therapy.

2020-05-13 | GSE150358 | GEO

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