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Carboplatin-mediated recovery of LPS-induced tolerant macrophages via H3K9me3 modifications

ABSTRACT: Following the re-exposure to lipopolysaccharide (LPS), macrophages exhibit the immunosuppressive state contribute to low production of proinflammatory cytokines and inability to respond the stimuli, a phenomenon is termed “tolerance”. Histone modification has been found in LPS-induced tolerant macrophages. Carboplatin, an antitumor drug, exerts its general effect on inhibition of DNA replication and transcription as well as epigenetic modification. Therefore, we hypothesized that carboplatin can be used to rescue the tolerance in macrophages. We found that carboplatin increases IL-6 but not TNF-α production in LPS-primed cells. The significant inductions were examined in carboplatin-treated tolerant macrophages evaluated by ELISA and qPCR. GSEA analyses revealed that p53 was the significant hallmark in both primed and tolerant RNA-Seq transcripts under carboplatin exposure while E2F ang G2/M were the upmost in negative hallmarks. HP1-α, heterochromatin protein 1, was significantly reduced in carboplatin-treated tolerant macrophages. The significant lower transcript of H3K9me3 methyltransferase, setdb2, was determined whereas kdm4d, demethylase encoding gene was significantly up-regulated in the presence of carboplatin in tolerant macrophages. Based on our data we suggested that carboplatin mediated upregulation of proinflammatory cytokine and rescue tolerance via the H3K9me3 modification. Carboplatin is potentially be a therapeutic drug for tolerance recovery in sepsis patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE179974 | GEO | 2021/11/10

REPOSITORIES: GEO

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Carboplatin-mediated recovery of LPS-induced tolerant macrophages via H3K9me3 modifications

Project description:Carboplatin-mediated recovery of LPS-induced tolerant macrophages via H3K9me3 modifications

| PRJNA745998 | ENA

Mitohormesis reprograms macrophage metabolism to enforce tolerance [BMDM_tolerance_RNAseq]

Project description:Macrophages generate mitochondrial reactive oxygen and electrophilic species (mtROS, mtRES) as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here, we demonstrate that both pharmacologically- and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state where stimulus-induced proinflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, hydroxyestrogen-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and proinflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mtROS and mtRES are TLR-dependent signaling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signaling and pharmacologically triggering mitohormesis represents a novel anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of proinflammatory gene transcription by mitochondria.

2021-04-04 | GSE169730 | GEO

Mitohormesis reprograms macrophage metabolism to enforce tolerance [BMDM_ChIPseq]

2021-04-04 | GSE169729 | GEO

Mitohormesis reprograms macrophage metabolism to enforce tolerance [vWAT_mac_RNAseq]

2021-04-04 | GSE169728 | GEO

Mitohormesis reprograms macrophage metabolism to enforce tolerance [BMDM_OHestrogen_RNAseq]

2021-04-04 | GSE169727 | GEO

LPS-induced gene expression in mouse small intestinal epithelial cells

Project description:Intestinal epithelial cells express the lipopolysaccharide (LPS) receptor Toll-like receptor (TLR4) and are responsive to LPS stimulation. Following LPS exposure, epithelial cells, similar to myeloid cells such as macrophages, acquire a state of tolerance. Innate immune tolerance is characterized by a lack of expression of proinflammatory genes in response to repeated stimulation. Tolerant epithelial cells, however, exhibit sustained expression of a distinct set of genes encoding for proteins involved in metabolism and homeostasis. This study comparatively analyzes the gene expression profile 6 hours after LPS stimulation (acute response) versus 6 hours LPS followed by 90 hours incubation in the absence of LPS (tolerant response). We used microarrays to detail the global program of gene expression under unstimulated (control), LPS stimulated (6 hours), and tolerant (96 hours) conditions. Three biological replicates each from naive cells, 6 hour LPS-stimulated cells, and 6 hour LPS-stimulated plus 90 hour LPS-free medium-incubated cells were examined and compared.

2010-08-29 | E-GEOD-23755 | biostudies-arrayexpress

LPS-induced gene expression in mouse small intestinal epithelial cells

2010-08-29 | GSE23755 | GEO

Transcription profiling of mouse naive and tolerant macrophages stimulated with LPS

Project description:The inflammatory response initiated by microbial products signaling through Toll-like receptors (TLRs) of the innate immune system is essential for host defense against infection. Because inflammation can be harmful to host tissues, the innate response is highly regulated. Negative regulation of TLR4, the receptor for bacterial lipopolysaccharide (LPS), results in LPS tolerance, defined as hyporesponsiveness to repeated stimulation with LPS. LPS tolerance is thought to protect the host from excessive inflammation by turning off TLR4 signal, which then shuts down TLR-induced genes. However, TLR signaling induces hundreds of genes with very different functions. We reasoned that genes with different functions should have different requirements for regulation. Specifically, genes encoding proinflammatory mediators should be transiently inactivated to limit tissue damage, while genes encoding antimicrobial effectors, which directly target pathogens, should remain inducible in tolerant cells to protect the host from infection. Using an in vitro system of LPS tolerance in macrophages, here we show that TLR-induced genes may indeed be divided into two distinct categories based on their functions and regulatory requirements. Further, we show these distinct groups are regulated by gene-specific, and not signal-specific mechanisms. Experiment Overall Design: We examined gene expression using affymetrix genechips in 3 groups of murine bone-marrow derived macrophages: Naive (untreated), Naive stimulated with LPS, and Tolerant stimulated with LPS. Two biological replicates were performed for each group.

2008-06-15 | E-GEOD-7348 | biostudies-arrayexpress

EED in the Polycomb Repressive Complex 2 Epigenetically Regulates Responses in Lipopolysaccharide Tolerized Macrophages

Project description:To avoid exaggerated inflammation and injury, host cells adapt to become hypo-responsive or “tolerance” in response to successive exposure to stimuli. Such tolerized response is a part of innate immune memory which is mainly regulated via epigenetics changes and metabolic reprograming. Polycomb repressive complex 2 (PRC2) mediates the transcriptional repression by catalyzing histone H3 lysine 27 trimethylation (H3K27me3) but little is known about the roles of PRC2 in tolerant macrophages. We examined the impact of PRC2 components, EED and Ezh2, on lipopolysaccharide (LPS)-induced tolerant macrophages. In Eed KO macrophages, not only the significant reduction in H3K27me3, but also the augmentation of an active histone mark, H3K27Ac. Upon EED deletion but not Ezh2, macrophages exhibited attenuated pro-inflammatory cytokines productions (TNF-α and IL-6) in LPS-tolerant cells. In addition, LPS tolerant Eed KO macrophages exhibited low glycolytic activity rather than its littermate wild-type control. RNA-Seq analyses revealed that most of differentially expressed genes are involved in oxidative phosphorylation and TGF-β signaling. Alteration of H3K27me3 and H3K27ac in the regulatory regions of some of these genes were validated. These results indicated that PRC2 via EED epigenetically suppresses these genes in response to LPS re-exposure and lacking PRC2 activity results in hypo-responsive to LPS re-stimulation. Therefore, we provide strong evidences that PRC2 via EED mediates LPS tolerance in macrophages by epigenetically suppressing proinflammatory responses with the link to dysregulated metabolic pathway.

2023-06-20 | GSE234655 | GEO

LPS tolerance in macrophages

Project description:Among the multiple mechanisms that control the intensity and duration of macrophage activation, the development of a state of refractoriness to a second stimulation in cells treated with LPS has long been recognized. Release of inhibitory cytokines and alterations in intracellular signaling pathways may be involved in the development of LPS tolerance. Although a number of molecules have been implicated, a detailed picture of the molecular changes in LPS tolerance is still missing. We have used a genome-wide gene expression analysis approach to (i) define which fraction of LPS target genes are subject to tolerance induction and (ii) identify genes that are expressed at high levels in tolerant macrophages. Our data show that in LPS tolerant macrophages the vast majority of LPS-induced gene expression is abrogated. The extent of tolerance induction varies for individual genes, and a small subset appears to be excepted. Compared to other negative control mechanisms of macrophages, e.g. IL-10-induced deactivation, LPS-tolerance inhibits a much wider range of transcriptional targets. Some previously described negative regulators of TLR-signaling (e.g. IRAK-M) were confirmed as expressed at higher levels in LPS-tolerant macrophages. In addition, we discuss other potential players in LPS tolerance identified in this group of genes. Keywords: pre and restimulation with LPS, tolerance induction

2007-08-10 | GSE8621 | GEO

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