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Itaconate regulates Th17/Treg cell balance via metabolic and epigenetic reprogramming [ATAC-seq]

ABSTRACT: An imbalance of T helper (Th17) cells and regulatory T (Treg) cells contributes to the pathogenesis of autoimmune diseases. The endogenous metabolite itaconate (ITA) is a regulator of macrophages; however, its role in T cells regulation is unclear. Here, we show that ITA inhibited Th17 cell differentiation and promoted Treg cell differentiation via metabolic and epigenetic reprogramming. Mechanistically, ITA suppressed glycolysis and mitochondrial respiration in Th17 and Treg-polarizing T cells. In Th17 cells, the S-adenosyl-L-methionine/ S-adenosylhomocysteine ratio was decreased following ITA administration in vitro, subsequently altering the epigenetic status. Further, ITA inhibited RORγt binding at the Il17a promoter, resulting in reduced IL-17A expression. In Treg cells, ITA reduced 2-hydroxyglutarate levels, which suppressed Foxp3 expression. The adoptive transfer of ITA-treated Th17-polarizing T cells ameliorated experimental autoimmune encephalomyelitis. Collectively, these results indicate that ITA serves as a crucial metabolic regulator for Th17/Treg cell balance and a potential therapeutic agent against autoimmune diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE207941 | GEO | 2023/01/18

REPOSITORIES: GEO

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Itaconate regulates Th17/Treg cell balance via metabolic and epigenetic reprogramming

Project description:An imbalance of T helper (Th17) cells and regulatory T (Treg) cells contributes to the pathogenesis of autoimmune diseases. The endogenous metabolite itaconate (ITA) is a regulator of macrophages; however, its role in T cells regulation is unclear. Here, we show that ITA inhibited Th17 cell differentiation and promoted Treg cell differentiation via metabolic and epigenetic reprogramming. Mechanistically, ITA suppressed glycolysis and mitochondrial respiration in Th17 and Treg-polarizing T cells. In Th17 cells, the S-adenosyl-L-methionine/ S-adenosylhomocysteine ratio was decreased following ITA administration in vitro, subsequently altering the epigenetic status. Further, ITA inhibited RORγt binding at the Il17a promoter, resulting in reduced IL-17A expression. In Treg cells, ITA reduced 2-hydroxyglutarate levels, which suppressed Foxp3 expression. The adoptive transfer of ITA-treated Th17-polarizing T cells ameliorated experimental autoimmune encephalomyelitis. Collectively, these results indicate that ITA serves as a crucial metabolic regulator for Th17/Treg cell balance and a potential therapeutic agent against autoimmune diseases.

2023-01-18 | GSE182895 | GEO

HIF1a-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells

Project description:Upon antigen stimulation, the bioenergetic demands of T cells increase dramatically over the resting state. Although a role for the metabolic switch to glycolysis has been suggested to support increased anabolic activities and facilitate T cell growth and proliferation, whether cellular metabolism controls T cell lineage choices remains poorly understood. Here we report that the glycolytic pathway is actively regulated during the differentiation of inflammatory TH17 and Foxp3-expressing regulatory T cells (Treg), and controls cell fate determination. TH17 but not Treg-inducing conditions resulted in strong upregulation of the glycolytic activity and induction of glycolytic enzymes. Blocking glycolysis inhibited TH17 development while promoting Treg cell generation. Moreover, the transcription factor hypoxia-inducible factor 1a (HIF1a) was selectively expressed in TH17 cells and its induction required signaling through mTOR, a central regulator of cellular metabolism. HIF1a-dependent transcriptional program was important for mediating glycolytic activity, thereby contributing to the lineage choices between TH17 and Treg cells. Lack of HIF1a resulted in diminished TH17 development but enhanced Treg differentiation, and protected mice from autoimmune CNS inflammation. Our studies demonstrate that HIF1a-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. Naïve CD4 T cells from wild-type and HIF1a-deficient mice (in triplicates each group) were differentiated under TH17 conditions for 2.5 days, and RNA was analyzed by microarrays.

2011-06-07 | E-GEOD-29765 | biostudies-arrayexpress

Itaconate is an inhibitor of TET DNA dioxygenases

Project description:Immune-response gene 1 (IRG1) transcription is rapidly induced by pathogen infections and inflammatory conditions primarily in cells of myeloid lineage. Deletion of Irg1 in mice causes severe defects in response to bacterial and viral infection and rapid death. IRG1 encodes a mitochondrial metabolic enzyme, aconitate decarboxylase 1 (ACOD1), that catalyzes the decarboxylation of cis-aconitate, a tricarboxylic acid cycle intermediate, to produce the anti-inflammatory metabolite itaconic acid (ITA). ITA can inhibit SDH5, resulting in elevated levels of succinate and metabolic reprogramming, or alkylate protein cysteine residues to induce electrophilic stress response mediated by NRF2 and IκBζ. Here we show that ITA is an antagonist of α-ketoglutarate (α-KG) and a potent inhibitor of α-KG/Fe2+-dependent TET family of DNA dioxygenases. In vitro, ITA binds to TET2 and inhibits the catalytic activity of TET2 and, reciprocally, α-KG blocks ITA binding to and inhibition of TET2. In vivo, lipopolysaccharides (LPS) treatment, which induces IRG1 expression and causes the intracellular accumulation of ITA, inhibits TET activity in Irg1-WT, but not Irg1-KO macrophages. Moreover, TET2 is a major target of ITA function in suppressing LPS-induced genes. LPS stimulates p65 NF-κB/RelA to bind with and recruit TET2 to hydroxymethylate and activate the Nfkbiz gene, which encodes IκBζ. Our results thus identify a physiological metabolite inhibitor of TET enzymes and reveal a novel mechanism for the anti-inflammatory function of ITA through dampening TET2-mediated NF-κB signaling.

2022-01-10 | GSE158580 | GEO

Epigenetic initiation of the Th17 differentiation programme is promoted by Cxxc finger protein 1

Project description:IL-6/STAT3 signalling is known to initiate the Th17 differentiation programme, but the upstream regulatory mechanisms remain minimally explored. Here, we show that Cxxc finger protein 1 (Cxxc1) promoted the generation and stability of Th17 cells as an epigenetic regulator and prevented their differentiation into Treg cells. Mice with a T cell-specific deletion of Cxxc1 were protected from experimental autoimmune encephalomyelitis and were more susceptible to Citrobacter rodentium infection. Cxxc1-deficient T cells acquired a Treg cell-biased programme that dominantly suppressed Th17 cell generation via IL-6Rα production. Cxxc1 deficiency decreased IL-6Rα expression and impeded IL-6/STAT3 signalling, whereas the overexpression of IL-6Rα could reverse the defects seen in Cxxc1-deficient Th17 cells in vitro and in vivo. Genome-wide occupancy analysis revealed that Cxxc1 bound to Il6rα gene loci in the Th17 programme by maintaining the appropriate H3K4me3 modification of its promoter. Therefore, these data highlight that Cxxc1 as a key regulator governs the balance between Th17 and Treg cells by controlling the expression of IL-6Rα, which subsequently affects IL-6/STAT3 signalling and has a direct impact on Th17-related autoimmune diseases.

2020-04-10 | GSE132208 | GEO

HIF1a-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells

2011-06-07 | GSE29765 | GEO

Expression data from Th17 cells of different origins

Project description:Foxp3 is indispensable for Treg suppressive function, but the stability of Foxp3 has been controversial. In autoimmune arthritis, Th17 cells play a critically important pathological role, but the origin of Th17 cells remains unknown We used microarrays to detail the global programme of gene expression of Th17 cells originated from Foxp3+T cells compared to conventional naive CD4+T cells derived Th17 cells. We also take samples of Treg cells and Th0 cells for the experimetnatl control. Each T cell subset after the culture was subjected to RNA extraction and hybridization on Affymetrix microarrays.

2013-12-21 | E-GEOD-48428 | biostudies-arrayexpress

Generation of RORγt+ antigen-specific T regulatory 17 (Tr17) cells from Foxp3+ precursors in autoimmunity

Project description:Th17 cells are potent mediators in autoimmune diseases and RORγt is required for their development. Recent studies have shown that RORγt+ Treg cells in the gut regulate intestinal inflammation by inhibiting effector T cell function. In the current study, we report that RORγt+ Treg cells were also found in lymph nodes following immunization. Not only distinct from intestinal RORγt+ Treg in their transcriptomes, peripheral RORγt+ Treg cells were derived from Foxp3+ thymic Treg cells, in an antigen-specific manner. Development of these RORγt+ Treg cells, coined as T regulatory 17 (Tr17) cells, depended on IL-6/Stat3 signaling. Tr17 cells showed suppressive activity against antigen-specific effector T cells in vitro. In addition, Tr17 cells efficiently inhibited myelin-specific Th17 cell-mediated CNS auto-inflammation in a passive EAE model. Collectively, our study demonstrates Tr17 cells as effector Treg cells that potentially restrict autoimmunity.

2017-08-31 | GSE103319 | GEO

Cyclic AMP-responsive element-binding protein (CREB) is critical in autoimmunity by promoting Th17 but inhibiting Treg differentiation

Project description:The molecular mechanisms that govern differential T cell development into pro-inflammatory Th17 vs. regulatory T (Treg) cells remain unclear. Here, we show that selective deletion of CREB in T cells or Th17 cells impaired Th17 differentiation in vitro and in vivo, and led to resistance to autoimmune diseases. Mechanistically, CREB, activated by CD3-PKC-ϴ signaling, plays a key role in regulating Th17 differentiation, at least in part through directly binding to the Il17-Il17f gene locus. Unexpectedly, although dispensable for FOXP3 expression and for the homeostasis and function of thymus-derived Treg cells, CREB negatively regulates the survival of TGF-β-induced Treg cells, and deletion of CREB resulted in increased FOXP3+ Treg cells in the intestine and protection in a colitis model. Thus, CREB is critical in autoimmune diseases by promoting Th17 and inhibiting de novo Treg generation.

2016-04-19 | GSE80375 | GEO

Sulforaphane protects from T cell mediated autoimmune disease by inhibition of interleukin 23 and 12 in dendritic cells

Project description:Sulforaphane (SFN), an isothiocyanate, is part of an important group of naturally occurring small molecules with antiinflammatory properties. Even though the published reports are vague, most are best conceivable with an inhibition of T cell functions. We therefore analyzed the effect of SFN on T cell-mediated autoimmune disease. Feeding mice with SFN protected from severe experimental autoimmune encephalomyelitis (EAE). Disease amelioration was associated with reduced interleukin (IL)-17 and IFN-gamma expression in draining lymph nodes. In vitro, SFN treatment of T cells did not directly alter T cell cytokine secretion. In contrast, SFN treatment of dendritic cells (DC) inhibited TLR4-induced IL-12 and IL-23 production and the cytokine profile of T cells stimulated by SFN-treated DC. SFN suppressed TLR4-induced nuclear factor kappa B (NFÎºB) activity, without affecting the degradation of its inhibitor (IÎºB). Instead, SFN treatment of DC resulted in strong expression of the stress response protein heme oxygenase-1 (HO-1), which interacts with NFÎºB p65 and inhibits its activity. Consistent with these findings, HO-1 bound to p65 and subsequently inhibited the p65 promoter activity within the IL23a and IL12b promoter region. Importantly, SFN suppressed Il23a and Il12b expression in vivo and silenced Th17/Th1 responses within the CNS . Our data show that SFN improves Th17/Th1-mediated autoimmune disease by inducing HO-1 and inhibiting p65-regulated IL-23 and IL-12 expression. Treatment-control experiment with two replicates per condition

2014-02-13 | E-GEOD-54980 | biostudies-arrayexpress

Expression data from Th17 cells of different origins

2013-12-21 | GSE48428 | GEO

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