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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.

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

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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.

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Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis

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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.

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

Project description:Monocytes can develop an exhausted memory state characterized by reduced differentiation, pathogenic inflammation, and immune suppression that drives immune dysregulation during sepsis. Chromatin alterations, notably via histone modifications, underlie innate immune memory, but the contribution of DNA methylation remains poorly understood. Using an ex vivo sepsis model, we show altered DNA methylation throughout the genome of exhausted monocytes, including genes implicated in immune dysregulation during sepsis and COVID-19 infection (e.g., Plac8). These changes are recapitulated in septic mice induced by cecal slurry injection. Methylation profiles developed in septic mice are maintained during ex vivo culture, supporting the involvement of DNA methylation in stable monocyte exhaustion memory. 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. Our study demonstrates the significance of altered DNA methylation in the maintenance of stable monocyte exhaustion memory.

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Project description:Monocyte exhaustion mediated by TRAM

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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