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Lipid droplet efferocytosis attenuates proinflammatory signaling in macrophages via TREM2 and MS4A7-dependent mechanisms

ABSTRACT: Lipid droplet efferocytosis attenuates proinflammatory signaling in macrophages via TREM2 and MS4A7-dependent mechanisms

PROVIDER: PRJNA1112445 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29060194_1.fastq.gz	Fastqsanger.gz
	SRR29060194_2.fastq.gz	Fastqsanger.gz
	SRR29060195_1.fastq.gz	Fastqsanger.gz
	SRR29060195_2.fastq.gz	Fastqsanger.gz
	SRR29060196_1.fastq.gz	Fastqsanger.gz

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Lipid droplet efferocytosis attenuates proinflammatory signaling in macrophages via TREM2 and MS4A7-dependent mechanisms

Project description:Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by the injury of steatotic hepatocytes, triggering the release of endogenous danger-associated molecular patterns (DAMP). The nature of the danger signals and their role in engaging the innate immune cells like macrophage remain to be fully delineated. Recent work demonstrated that exposed lipid droplets (LD) serve as a disease-associated danger signal that promotes monocyte infiltration and its maturation into TREM2+ macrophages within the MASH liver. In this study, we explored the nature of LD-mediated danger signaling and its impact on inflammatory signaling in macrophages. We found that efferocytosis of LDs triggers a global transcriptional response and dampens pro-inflammatory signaling in cultured macrophages. LD treatments attenuated proinflammatory signaling and NLRP3 inflammasome activation via mechanisms independent of lipid hydrolysis by macrophages. TREM2 is required for the attenuation of inflammatory response, whereas MS4A7 downregulation contributes to the dampening effects of LD treatments. These results underscore the dual role of LD-mediating danger signaling in MASH liver by promoting monocyte infiltration and TREM2+ macrophage induction and dampening pro-inflammatory response in macrophages.

2025-04-16 | GSE267716 | GEO

Lack of TREM2 during anti-PD-1 therapy reprograms intestinal macrophages and microbiota to enhance tumor rejection

Project description:The gut microbiota and tumor-associated macrophages (TAM) impact anti-PD-1 checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor TREM2 attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti-PD-1. Here, we found that anti-PD-1 combined with TREM2 deficiency induces proinflammatory programs in intestinal macrophages and a concomitant expansion of Ruminococcus gnavus (R. gnavus) in the gut microbiota. Gavage of wild-type mice with R. gnavus recapitulated enhancement of anti-PD-1-mediated tumor elimination occurring in the absence of TREM2. The intestinal proinflammatory environment coincided with expansion, increased circulation and migration of TNF-producing CD4+ T cells to the tumor bed. Thus, TREM2 remotely controls anti-PD-1 checkpoint blockade through modulation of the intestinal immune environment and microbiota, with R. gnavus emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.

2024-05-17 | GSE262811 | GEO

Trem2 Macrophage Promote Cardiac Repair in Myocardial Infarction via Efferocytosis and Carbohydrate Metabolism

Project description:Trem2 Macrophage Promote Cardiac Repair in Myocardial Infarction via Efferocytosis and Carbohydrate Metabolism

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AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation

Project description:We identified enrichment of a disease-enhancing, proinflammatory subpopulation of microglia in human AD patient brains with the R47H-TREM2 mutation, and uncovered that enhanced Akt signaling in microglia underlies the proinflammatory cytokine state and synaptic toxicity in our R47H-TREM2 tauopathy mouse model.

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AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation [Hs]

2022-01-07 | GSE183068 | GEO

Trem2 Macrophage Promote Cardiac Repair in Myocardial Infarction via Efferocytosis and Carbohydrate Metabolism

Project description:We want to find that the TREM2 mechanism on the Macrophages in the myocardial infarction

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AD-linked TREM2 mutation induces disease-enhancing proinflammatory microglial states in mice and humans [Now it is part of GSE183068]

Project description:The hemizygous R47H variant of TREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). To understand its pathogenicity, we performed single-nuclei RNA-sequencing of cortical tissue from AD patients with R47H or the common variant (CV)-TREM2 with matched sex, pathology and APOE status. we found that the R47H mutation is associated with cell type- and sex-specific transcriptional changes in human AD, with microglia exhibiting the most robust alterations. R47H-associated microglial subpopulations were characterized by hyperactivation of AKT, one of the signaling pathways downstream of TREM2, and enhanced inflammatory signatures. In tauopathy mouse models that carry one allele of human TREM2 (hTREM2) with either the R47H mutation or CV, the mutation induced spatial memory deficits and exacerbated tau-mediated deficits in female mice. Similar to the human data, the disease-enhancing effects of R47H microglia were associated with robust increases in proinflammatory cytokines, Syk-Akt-signaling, and elevation of a subset of disease-associated microglial signatures identified using single-cell sequencing from isolated microglia. Pharmacological Akt inhibition largely reversed the enhanced inflammatory signatures in R47H microglia treated with tau fibrils. By unraveling the disease-enhancing properties of the R47H mutation in mouse and human, our findings shed light on an immune-linked AD subtype and provide new directions for modulating brain immune responses to treat AD.

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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

Study of human macrophage reprogramming toward a pro-resolving profile by efferocytosis

Project description:Inﬂammation is a physiopathological process triggered by infection or tissue damage. Immune system initiates coordinated sequential steps in response to these danger signals. Once the threat has been contained inflammation has to be subsequently shut down. Inflammation resolution is initiated by the reprogramming of pro-inflammatory macrophages toward a pro-resolving profile. This reprogramming is induced in particular by the non-phlogistic engulfment of apoptotic cells, mostly apoptotic neutrophils, a process called efferocytosis. As a matter of fact, macrophages are an essential linchpin regulating both inflammation triggering and sustaining and inflammation resolution. This duality can be achieved through the tremendous plasticity of these innate immune cells. Indeed, depending on microenvironmental signals (cytokines, efferocytosis, growth factors…) macrophages can adopt numerous diverse and sometimes antagonistic phenotypes. The mechanisms governing these transitions remain relatively scattered especially in human. With this project we propose to explore the mechanisms involved in human macrophage reprogramming toward a pro-resolving profile after efferocytosis. The stakes are high due to the estimated prevalence of chronic inflammatory diseases in Western society is 5 to 7%. Chronic inflammation is a burden to patient due to life-long debilitating illness and increased mortality and is also a burden to society due to high costs for therapy and care. Finding new therapies to limit chronic inflammation establishment and persistence is thus a highly valuable goal.

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TREM2 inhibition triggers anti-tumor cell activity of myeloid cells in glioblastoma [scRNA]

Project description:The prevailing view is that myeloid cells in the tumor microenvironment (TME) are immunosuppressive and promote glioblastoma (GBM) progression. However, myeloid cells have the functional plasticity to restrict or support tumor cell growth. TREM2 plays important roles in brain microglial function in neurodegenerative diseases, but the role of TREM2 in the GBM TME has not been examined. We found TREM2 is highly expressed in myeloid subsets, including macrophages and microglia in human and mouse GBM tumors and that high TREM2 expression correlates with poor prognosis in GBM patients. TREM2 loss of function in human macrophages and mouse myeloid cells increased tumoricidal capacity. TREM2 in myeloid cells restricts IFNγ-induced immunoactivation and proinflammatory polarization. In orthotopic mouse GBM models, Trem2-/- mice and mice with acute brain Trem2 reduction demonstrate survival benefit. Trem2 inhibition reprograms myeloid phenotypes and increases PD-1+CD8+ T cells in the TME. Trem2 deficiency enhances the effectiveness of anti-PD-1 treatment and may represent a therapeutic strategy for GBM patients.

2023-05-12 | GSE226292 | GEO

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