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Monocyte exhaustion mediated by TRAM

ABSTRACT: Monocyte exhaustion mediated by TRAM

PROVIDER: PRJNA755992 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15510606.fastq.gz	Fastqsanger.gz
	SRR15510607.fastq.gz	Fastqsanger.gz
	SRR15510608.fastq.gz	Fastqsanger.gz

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Monocyte exhaustion mediated by TRAM

Project description:We performed single cell sequencing analysis of exhausted monocytes generated in vitro through prolonged incubation with high dose LPS. We demonstated that 5-day prolonged stimulation of WT but not TRAM KO monocytes with high dose LPS drastically induced monocyte exhaustion, as reflected in higher levels of inflammatory marker genes such as CD38 and immuno-suppressor genes including PD-L1.

2021-10-22 | GSE182355 | GEO

TRAM deletion attenuates monocyte exhaustion and alleviates sepsis severity.

Project description:Monocyte exhaustion characterized by immune-suppressive features can develop during sepsis and contribute to adverse patient outcomes. However, molecular mechanisms responsible for the establishment of immune-suppressive monocytes with reduced expression of immune-enhancing mediators such as CD86 during sepsis are not well understood. In this study, we identified that the TLR4 intracellular adaptor TRAM plays a key role in mediating the sustained reduction of CD86 expression on exhausted monocytes and generating an immune-suppressive monocyte state. TRAM contributes to the prolonged suppression of CD86 through inducing TAX1BP1 as well as SARM1, collectively inhibiting Akt and NFκB. TRAM deficient mice are protected from cecal slurry-induced experimental sepsis and retain immune-competent monocytes with CD86 expression. Our data reveal a key molecular circuitry responsible for monocyte exhaustion and provide a viable target for rejuvenating functional monocytes and treating sepsis.

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Alleviation of monocyte exhaustion by BCG derivative mycolic acid

Project description:Monocyte exhaustion characterized by sustained pathogenic inflammatory and immune-suppressive features underlies the pathogenesis of sepsis induced by systemic polymicrobial infections. However, effective strategies in blocking monocyte exhaustion and restoring innate homeostasis are currently not available. In this study, we found that Methoxy-Mycolic Acid (M-MA), a branched mycolic acid derived from Mycobacterium Bovis Bacillus Calmette–Guérin (BCG), to be a potent agent in alleviating monocyte exhaustion and restoring immune homeostasis. Co-treatment of monocytes with M-MA can effectively block the expansion of exhausted Ly6Chi /CD38hi/PD-L1hi monocytes induced by repetitive LPS challenges, and restore the expression of immune-enhancing CD86 on co-treated monocytes. Functionally, M-MA treatment restored mitochondrial functions of exhausted monocytes and alleviated their suppressive activities on co-cultured T cells. Mechanistically, M-MA exerts its protective effects independent of cellular receptor TREM2, and relieves cellular stress signaling through blocking Src-STAT1 mediated pathogenic inflammatory polarization as well as reducing the production of compensatory immune suppressors TAX1BP1 and PLAC8. Our whole genome methylation analyses further revealed that M-MA can effectively erase methylation memory of exhausted monocytes, with validated restoration of plac8 methylation by M-MA. Together, our data reveal M-MA as a potent agent in restoring monocyte homeostasis with future therapeutic potential for the treatment of sepsis.

2023-12-19 | GSE242825 | GEO

Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis

Project description:Sepsis is a leading cause of death worldwide, with most patient mortality stemming from lingering immunosuppression in sepsis survivors. This is due in part to immune dysfunction stemming from monocyte exhaustion, a phenotype of reduced antigen presentation, altered CD14/CD16 inflammatory subtypes, and disrupted cytokine production. Whereas previous research demonstrated improved sepsis survival in Ticam2-/- mice, the contribution of TICAM2 signaling to long-term exhaustion memory was unknown. Using a cecal slurry injection sepsis model, we monitored the establishment and recovery of monocyte exhaustion in Ticam2-/- mice. Like wild-type controls, Ticam2-/- monocytes develop an exhaustion phenotype defined by CD38high; CX3CR1low; MHCIIlow cell surface expression 48 hours after sepsis onset. Time course analysis of sepsis patient blood samples revealed a similar effect in human monocytes, which steadily transition into a CD38high; CX3CR1low; HLA-DRlow state within four days of hospital admittance. To determine the impact of TICAM2 ablation on innate epigenetic memory in sepsis, we measured genome-wide DNA methylation in bone marrow monocytes and found that Ticam2-/- cells exhibit a unique profile of altered methylation at CEBPE binding sites and regulatory features for key immune genes such as Dmkn and Btg1. Finally, after one week of sepsis recovery, we profiled bone marrow and splenic reservoir monocytes in Ticam2-/- mice and found that, in contrast to the persistent exhaustion observed in wild-type monocytes, Ticam2-/- monocytes largely resembled healthy controls. Thus, in addition to improving survival during the inflammatory phase of sepsis progression, TICAM2 ablation facilitates the resolution of monocyte exhaustion in sepsis survivors.

2025-01-21 | GSE271939 | GEO

Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis

Project description:Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis

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Alleviation of monocyte exhaustion by BCG derivative mycolic acid

Project description:Alleviation of monocyte exhaustion by BCG derivative mycolic acid

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Resolving monocytes generated through TRAM deletion attenuate the pathogenesis of atherosclerosis

Project description:We performed scRNAseq analysis of murine monocytes cultured from bone marrow isolates of WT and TRAM knockout mice. WT and TRAM knockout monocytes were cultured in vitro for 5 days in the presence or absence of low dose LPS (100 pg/ml).

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Generation of resolving neutrophils with 4-PBA or genetic deletion of TRAM

Project description:We have generated resolving neutrophils with anti-inflammatory potency, through applying the pharmacological agent 4-PBA or genetically depleting TRAM molecule. WT murine neutrophils treated with PBS or 4-PBA for overnight were harvested for scRNAseq analysis to examine the generated resolving neutrophil phenotype. In addtion, we have cultured WT and TRAM KO neutrophils and compared the resolving phenotype via scRNAseq analysis.

2022-04-20 | GSE182356 | GEO

M-TraM analysis for identification of chlorhexidine resistance genes in Enterococcus faecium E1162

Project description:Microarray-based Transposon Mapping (M-TraM) of E. faecium E1162 to identify conditionally essential genes, required for growth in the presence of chlorhexidine (1.2 ug/ml)

2016-07-03 | E-MTAB-4173 | biostudies-arrayexpress

Altered DNA methylation underlies monocyte dysregulation and immune exhaustion memory in sepsis

Project description:Altered DNA methylation underlies monocyte dysregulation and immune exhaustion memory in sepsis

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