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Altered DNA methylation underlies monocyte dysregulation and immune exhaustion memory in sepsis [CUT&RUN]

ABSTRACT: Altered DNA methylation underlies monocyte dysregulation and immune exhaustion memory in sepsis [CUT&RUN]

PROVIDER: PRJNA1064414 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27536900_1.fastq.gz	Fastqsanger.gz
	SRR27536900_2.fastq.gz	Fastqsanger.gz
	SRR27536883_1.fastq.gz	Fastqsanger.gz
	SRR27536883_2.fastq.gz	Fastqsanger.gz
	SRR27536884_1.fastq.gz	Fastqsanger.gz

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

Project description:Innate immune memory is the process by which pathogen exposure elicits cell-intrinsic states to alter the strength of future immune challenges. Such altered memory states drive monocyte dysregulation during sepsis, promoting pathogenic behavior characterized by pro-inflammatory, immunosuppressive gene expression and emergency hematopoiesis. Epigenetic changes, notably via histone modifications, have been shown to underlie innate immune memory, but the contribution of DNA methylation remains poorly understood. Using an ex vivo sepsis model, we discovered broad changes in DNA methylation throughout the genome of exhausted monocytes, including at several genes implicated in immune dysregulation during sepsis and Covid-19 infection (e.g. Plac8). Methylome reprogramming is driven in part by Wnt signaling inhibition in exhausted monocytes, and can be reversed with DNA methyltransferase inhibitors, Wnt agonists, or immune training molecules. These changes are recapitulated in septic mice following cecal slurry injection, supporting the involvement of DNA methylation in acute and long-term monocyte dysregulation during sepsis.

2024-03-05 | GSE242816 | GEO

Altered DNA methylation underlies monocyte dysregulation and immune exhaustion memory in sepsis [CUT&RUN]

2024-03-05 | GSE253201 | GEO

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-03-05 | GSE253202 | GEO

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

Gut-mediated immune exhaustion increases vulnerability to sepsis during pregnancy

Project description:Pregnancy appears to accelerate mortality associated with infectious diseases; however, the underlying mechanism of the crosstalk between pregnancy and sepsis remains poorly understood. Integrated multiomics analysis of gut microbiome revealed that the abundances of Parabacteroides merdae and its-derived formononetin (FMN) were decreased during pregnancy. Here, we verified that gut microbiota dysbiosis during pregnancy exacerbated immune exhaustion caused by sepsis through accelerating macrophage pyroptosis. Mechanistically, FMN suppressed nucleus-accumulation of hnRNPUL2 to prevent it from binding to Nlrp3 promoter region, thus to inhibit priming of NLRP3 inflammasome. Genetic knockdown of murine hnRNPUL2 by an adeno-associated virus protected against sepsis. Intriguingly, the abundances of Parabacteroides merdae and FMN in feces were negatively correlated with the progression of septic patients. Our data highlighted the significance of FMN/hnRNPUL2/NLRP3 axis mediated by dysbiosis of Parabacteroides merdae in immune exhaustion of pregnant septic hosts, shedding light on promising therapeutic strategies for the treatment of sepsis.

2021-12-27 | PXD030649 |

Gut Microbial Dysbiosis Underlies Immune Dysregulation in CVID

Project description:Gut Microbial Dysbiosis Underlies Immune Dysregulation in Common Variable Immunodeficiency

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Monocyte exhaustion mediated by TRAM

Project description:Monocyte exhaustion mediated by TRAM

| PRJNA755992 | ENA

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

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