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Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE250273 | GEO | 2024/02/19

REPOSITORIES: GEO

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Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids

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

Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation

Project description:Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation mechanism accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the downstream pro-inflammatory IL-1Î²-HIF1a axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions via its effect on succinate dehydrogenase, by inhibiting conversion of succinate to fumarate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1-/- mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, changes in mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages. Experiment 1: mature WT BMDM were treated for 12h with 0.25 mM dimethyl itaconate (DI) or vehicle (Unst) and then stimulated with LPS (E. coli 0111:B4; 100 ng/ml, 4h) (DI+LPS; LPS); Experiment 2: mature Irg1-/- BMDM were stimulated with LPS (E. coli 0111:B4; 100 ng/ml) and murine recombinant IFNg (50 ng/ml) for 24h.

2016-07-01 | E-GEOD-82043 | biostudies-arrayexpress

Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation

Project description:Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation mechanism accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the downstream pro-inflammatory IL-1β-HIF1a axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions via its effect on succinate dehydrogenase, by inhibiting conversion of succinate to fumarate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1-/- mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, changes in mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages.

2016-07-01 | GSE82043 | GEO

Succinate mediates inflammation-induced adrenocortical dysfunction

Project description:Inflammation leads the hypothalamus-pituitary-adrenal (HPA) axis activation and increased production of glucocorticoids, which produced by the adrenal cortex, exert potent anti-inflammatory effects. The use of omics, including proteomics revealed metabolic changes in steroidogenic adrenocortical cells, including downregulation of the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, decreased ATP production and induction of oxidative stress after lipopolysaccharide (LPS)-induced inflammation.

2023-07-21 | PXD036542 | Pride

Effects of Acod1 loss on liver responses to fat overnutrition

Project description:ACOD1 is the enzyme repurposing cisaconitate from the tricarboxylic acid (TCA) cycle in the mitochondria to produce itaconate, a metabolite with anti-inflammatory and tolerogenic functions. In particular, itaconate accumulation in macrophages is known to oppose pro-inflammatory cytokine production mainly by inhibiting succinate dehydrogenase activity, activating the NRF2 and ATF3driven responses and inhibiting NLRP3. Itaconate biosynthesis was found to be induced in the liver of mice exposed to ischemia reperfusion (I/R) stress and to oppose the resulting tissue injury by sustaining hepatoprotective antioxidant programs. Whether ACOD1 plays a role in the homeostatic response of liver to different noninfectious injuring conditions remains largely unexplored. This study investigates the contribution of itaconate biosynthesis in the response of liver to dietary lipid overload and in the development of associated nonalcoholic fatty liver disease.

| MSV000090276 | MassIVE

Nitric oxide modulates metabolic remodelling and immunometabolism in inflammatory murine macrophages

Project description:Classical stimulation of macrophages (MLPS/IFNγ) elicits the expression of inducible nitric oxide synthase (iNOS), generating large amounts of nitric oxide (NO) and inhibiting respiration. Consequent upregulation of glycolysis and a disrupted tricarboxylic acid (TCA) cycle underpin this switch to a pro-inflammatory phenotype. Here we show that the NOS cofactor tetrahydrobiopterin (BH4) modulates key aspects of metabolic remodelling in activated bone-marrow-derived macrophages (BMDMs) via NO production. Using two complementary mouse models that each lack the capacity for inducible NO generation, through different mechanisms, we reveal that NO regulates macrophage respiratory function via changes in the abundance of critical N-module subunits in Complex I, by HIF1α-mediated glycolytic remodelling, and by modulating levels of the critical TCA cycle metabolites, and inflammatory mediators, citrate, succinate, and itaconate. Taken together, our findings reveal new critical roles for iNOS-derived NO that are required for metabolic remodelling and cytokine production in macrophage inflammatory responses.

2019-05-31 | PXD010628 | Pride

Sexual Dimorphic Regulation of Liver Gene Expression by Glucocorticoids

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

Myeloid-derived suppressor cells mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies

Project description:Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlated with poor outcomes in hematologic malignancies. Here, we identify the mitochondrial fitness in MDSCs controlling the efficacy of doxorubicin chemotherapy for lymphoma. Mechanistically, we show that triggering STAT3 signaling via β2-adrenergic receptor (β2-AR) activation leads to metabolic reprograming of MDSCs, marked by sustained mitochondrial respiration (OX/PHOS) and higher ATP generation which reduces the AMPK signaling. Furthermore, induced STAT3 signaling in MDSCs enhanced glutamine consumption via the tricarboxylic acid (TCA) cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species (mROS) via regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the antioxidant machinery. We found that targeting the STAT3 pathway or ATP/Itaconate metabolites by blocking β2-AR signaling, the electron transport chain and ATP generation, or itaconate generation, results in disrupted MDSC mitochondrial fitness. This disruption increases the in vivo response to doxorubicin, delaying lymphoma progression.

2024-02-29 | GSE254512 | GEO

Changes in nascent transcripts upon glucocorticoid stimulation in macrophages

Project description:Glucocorticoids are widely prescribed anti-inflammatory drugs with tissue-specific effects. Beneficial anti-inflammatory effects are caused in cells of the immune system whereas metabolic adverse effects of glucocorticoid therapy are seen in metabolic tissues such as liver. The glucocorticoid receptor (GR), a nuclear receptor targeted by glucocorticoids, bind its DNA response elements upon ligand exposure in a tissue-specific manner. Tissue-specific GR binding patterns depend on the access of its binding sites, which determines the tissue-specific glucocorticoid response. Here, we investigated this response by nascent RNAseq in murine bone marrow-derived macrophages (BMDMs) after stimulation with lipopolysaccharide (LPS) and dexamethasone (Dex). After labelling newly synthesized transcripts with 4-thiouracile (4sU), we identified macrophage-specific non-coding transcripts expressed at intergenic GR binding sites. Those transcripts are regulated by the GR and correlate with its anti-inflammatory function in macrophages. Those findings add another layer to the mechanisms underpinning GR's tissue-specific gene regulation and represent potential drug targets in anti-inflammatory therapy and/or management of adverse effects in glucocorticoid therapy.

2021-12-31 | GSE186629 | GEO

The auophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages

Project description:Glucocorticoids are widely used to treat inflammatory disorders; however, prolonged use of glucocorticoids results in side effects including osteoporosis, diabetes and obesity. Compound A (CpdA), identified as a selective NR3C1/glucocorticoid receptor (nuclear receptor subfamily 3, group C, member 1) modulator, exhibits an inflammation-suppressive effect, largely in the absence of detrimental side effects. To understand the mechanistic differences between the classic glucocorticoid dexamethasone (DEX) and CpdA, we looked for proteins oppositely regulated in bone marrow-derived macrophages using an unbiased proteomics approach. We found that the autophagy receptor SQSTM1 but not NR3C1 mediates the anti-inflammatory action of CpdA. CpdA drives SQSTM1 upregulation by recruiting the NFE2L2 transcription factor to its promoter. In contrast, the classic NR3C1 ligand dexamethasone recruits NR3C1 to the Sqstm1 promoter and other NFE2L2-controlled gene promoters, resulting in gene downregulation. Both DEX and CpdA induce autophagy, with marked different autophagy characteristics and morphology. Suppression of LPS-induced Il6 and Ccl2 genes by CpdA in macrophages is hampered upon Sqstm1 silencing, confirming that SQSTM1 is essential for the anti-inflammatory capacity of CpdA, at least in this cell type. Together, these results demonstrate how off-target mechanisms of selective NR3C1 ligands may contribute to a more efficient anti-inflammatory therapy.

2019-06-11 | PXD012121 | Pride

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