Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids
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PROVIDER: PRJNA1053278 | ENA |
REPOSITORIES: ENA
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Project description:Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids
| PRJNA1053280 | ENA
Project description:Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases (IMIDs). However, molecular mechanisms underlying their anti inflammatory mode of action have remained incompletely understood. Here we show that the anti-inflammatory properties of glucocorticoids involve a reprogramming of the mitochondrial metabolism of macrophages, which results in an increased and sustained production of the anti-inflammatory metabolite itaconate and a consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex where glucocorticoids provoke an increase in activity and allow an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. Artificial block of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, in contrast, interferes with the anti-inflammatory effects of glucocorticoids and accordingly abrogates their beneficial effects during a diverse range of preclinical models of IMIDs. Our findings provide important additional insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the future design of novel classes of anti-inflammatory drugs.
2024-02-19 | GSE250273 | GEO
Project description:Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases (IMIDs). However, molecular mechanisms underlying their anti inflammatory mode of action have remained incompletely understood. Here we show that the anti-inflammatory properties of glucocorticoids involve a reprogramming of the mitochondrial metabolism of macrophages, which results in an increased and sustained production of the anti-inflammatory metabolite itaconate and a consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex where glucocorticoids provoke an increase in activity and allow an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. Artificial block of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, in contrast, interferes with the anti-inflammatory effects of glucocorticoids and accordingly abrogates their beneficial effects during a diverse range of preclinical models of IMIDs. Our findings provide important additional insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the future design of novel classes of anti-inflammatory drugs.
2024-02-19 | GSE250274 | GEO
Project description:Recent studies have demonstrated that upon encountering a pathogenic stimulus, robust metabolic rewiring of immune cells occurs. A switch away from oxidative phosphorylation to glycolysis, even in the presence of sufficient amounts of oxygen (akin the Warburg effect), is typically observed in activated innate and adaptive immune cells and is thought to accommodate adequate inflammatory responses. However, whether the Warburg effect is a general phenomenon applicable in human monocytes exposed to different pathogenic stimuli is unknown. Our results using human monocytes from healthy donors demonstrate that the Warburg effect only holds true for TLR4 activated cells. Although activation of other TLRs leads to an increase in glycolysis, no reduction or even an enhancement in oxidative phosphorylation is observed. Moreover, specific metabolic rewiring occurs in TLR4 vs. TLR2 stimulated cells characterized by altered gene expression profiles of pathways related to metabolism, changes in spare respiratory capacity of the cells and differential regulation of mitochondrial enzyme activity. Similarly, results from ex vivo and in vivo studies demonstrate metabolic rewiring of immune cells that is highly dependent on the type of pathogenic stimulus. Although the Warburg effect is observed in human monocytes after TLR4 activation, we propose that this typical metabolic response is not applicable to other inflammatory signalling routes including TLR2 in human monocytes. Instead, each pathogenic stimulus and subsequently activated inflammatory signalling cascade induces specific metabolic rewiring of the immune cell to accommodate an appropriate response.
2016-10-19 | GSE78699 | GEO
Project description:In macrophages, homeostatic and immune signals induce distinct sets of transcriptional responses, defining the cellular identity and function. The activity of lineage specific and signal induced transcription factors are regulated by chromatin accessibility and other epigenetic modulators. Glucocorticoids are potent anti-inflammatory drugs. Acting through the glucocorticoid receptor (GR), glucocorticoids directly repress inflammatory responses at transcriptional and epigenetic levels in macrophages. In this study, we identified bromodomain containing 9 (BRD9), a component of SWI/SNF chromatin remodeling complex, as a novel modulator for glucocorticoids responses in macrophages. Inhibition, degradation, or genetic depletion of BRD9 in bone marrow derived macrophages (BMDM), significantly compromised their responses to inflammatory stimuli, such as liposaccharides (LPS), and interferons. A large portion of BRD9-regulated genes are also known to be regulated by dexamethasone, a synthetic glucocorticoid. Importantly, pharmacologic inhibition of BRD9 is able to further potentiate the anti-inflammatory responses of dexamethasone, by further repressing the GR downstream targets. Mechanistically, BRD9 co-localized with a subset of GR binding sites. Depletion of BRD9 enhanced GR occupancy at a subset of its targets. Enhanced occupancy of GR at these sites is associated with further repression of inflammation-related genes. Collectively, these findings establish BRD9 as a key modulator of macrophage inflammatory responses, revealing the therapeutic potential of BRD9 inhibitors as modulators for glucocorticoids action.
2021-08-23 | GSE175584 | GEO
Project description:In macrophages, homeostatic and immune signals induce distinct sets of transcriptional responses, defining the cellular identity and function. The activity of lineage specific and signal induced transcription factors are regulated by chromatin accessibility and other epigenetic modulators. Glucocorticoids are potent anti-inflammatory drugs. Acting through the glucocorticoid receptor (GR), glucocorticoids directly repress inflammatory responses at transcriptional and epigenetic levels in macrophages. In this study, we identified bromodomain containing 9 (BRD9), a component of SWI/SNF chromatin remodeling complex, as a novel modulator for glucocorticoids responses in macrophages. Inhibition, degradation, or genetic depletion of BRD9 in bone marrow derived macrophages (BMDM), significantly compromised their responses to inflammatory stimuli, such as liposaccharides (LPS), and interferons. A large portion of BRD9-regulated genes are also known to be regulated by dexamethasone, a synthetic glucocorticoid. Importantly, pharmacologic inhibition of BRD9 is able to further potentiate the anti-inflammatory responses of dexamethasone, by further repressing the GR downstream targets. Mechanistically, BRD9 co-localized with a subset of GR binding sites. Depletion of BRD9 enhanced GR occupancy at a subset of its targets. Enhanced occupancy of GR at these sites is associated with further repression of inflammation-related genes. Collectively, these findings establish BRD9 as a key modulator of macrophage inflammatory responses, revealing the therapeutic potential of BRD9 inhibitors as modulators for glucocorticoids action.
2021-08-23 | GSE175583 | GEO
Project description:In macrophages, homeostatic and immune signals induce distinct sets of transcriptional responses, defining the cellular identity and function. The activity of lineage specific and signal induced transcription factors are regulated by chromatin accessibility and other epigenetic modulators. Glucocorticoids are potent anti-inflammatory drugs. Acting through the glucocorticoid receptor (GR), glucocorticoids directly repress inflammatory responses at transcriptional and epigenetic levels in macrophages. In this study, we identified bromodomain containing 9 (BRD9), a component of SWI/SNF chromatin remodeling complex, as a novel modulator for glucocorticoids responses in macrophages. Inhibition, degradation, or genetic depletion of BRD9 in bone marrow derived macrophages (BMDM), significantly compromised their responses to inflammatory stimuli, such as liposaccharides (LPS), and interferons. A large portion of BRD9-regulated genes are also known to be regulated by dexamethasone, a synthetic glucocorticoid. Importantly, pharmacologic inhibition of BRD9 is able to further potentiate the anti-inflammatory responses of dexamethasone, by further repressing the GR downstream targets. Mechanistically, BRD9 co-localized with a subset of GR binding sites. Depletion of BRD9 enhanced GR occupancy at a subset of its targets. Enhanced occupancy of GR at these sites is associated with further repression of inflammation-related genes. Collectively, these findings establish BRD9 as a key modulator of macrophage inflammatory responses, revealing the therapeutic potential of BRD9 inhibitors as modulators for glucocorticoids action.
2021-08-23 | GSE175582 | GEO
Project description:Glucocorticoids (GCs) are widely used as anti-inflammatory drugs, but their long-term use has severe metabolic side effects. Here, by treating multiple patient-derived adipose stem cell-derived adipocytes and iPSC-derived hepatocytes with the potent GC dexamethasone (Dex), we uncovered cell type-specific and individual-specific GC-dependent transcriptomes and glucocorticoid receptor (GR) cistromes. Patient-specific GR binding could be traced to single nucleotide polymorphisms (SNPs) that altered the binding motifs of GR or its cooperating factors. We also discovered another set of genetic variants that modulated Dex response through affecting chromatin accessibility or chromatin architecture. Several SNPs that altered Dex-regulated GR binding and gene expression controlled Dex-driven metabolic perturbations and, remarkably, predicted metabolic side-effects of GC-treated patients. These data validate a patient stem cell-based experimental framework to discover genetic variants that impact GR function and individual responses to GC drugs, with implications for developing personalized therapies.
2021-06-23 | GSE163061 | GEO
Project description:Males and females exhibit differences in the incidence of many major diseases including auto-immune diseases, hepatocellular carcinoma, diabetes, and osteoporosis, which all have important inflammatory components in their etiology. Glucocorticoids are the primary physiological anti-inflammatory hormone in all mammals and synthetic derivatives of these hormones are widely prescribed as anti-inflammatory agents irrespective of gender. Surprisingly we report a marked sexually dimorphic regulation of gene expression by glucocorticoids in the rat liver. Eight distinct patterns of glucocorticoid regulated genes were identified and two revealed genes that respond to glucocorticoid treatment in both sexes in opposite directions (anti-correlated genes. We also identified gender-specific groups of genes regulated by glucocorticoids. Pathways analysis identified sex-specific glucocorticoid regulated gene expression in several canonical pathways that have been implicated in human disease in which disease susceptibility is sex-biased. For example, comparison of number of genes involved in inflammatory disorders between sexes, revealed 84 additional glucocorticoid responsive genes in the male rat. Our data suggests that glucocorticoids thorough sexually-dimorphic regulation of gene expression modulate gender specific homeostatic functions in male and female liver.
2010-10-02 | GSE13461 | GEO
Project description:Repair of airway epithelia requires metabolic rewiring towards fatty acid oxidation
2023-01-31 | GSE218663 | GEO