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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE29765 | GEO | 2011/06/07

SECONDARY ACCESSION(S): PRJNA141031

REPOSITORIES: GEO

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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

SIRT3 opposes metabolic reprogramming of cancer cells through HIF1a destabilization

Project description:Tumor cells exhibit aberrant metabolism characterized by high glycolysis even in the presence of oxygen. This metabolic reprogramming, known as the Warburg effect, provides tumor cells with the substrates and redox potential required for the generation of biomass. Here, we show that the mitochondrial NAD-dependent deacetylase SIRT3 is a crucial regulator of the Warburg effect. SIRT3 loss promotes a metabolic profile consistent with high glycolysis required for anabolic processes in vivo and in vitro. Mechanistically, SIRT3 mediates metabolic reprogramming independently of mitochondrial oxidative metabolism and through HIF1a, a transcription factor that controls expression of key glycolytic enzymes. SIRT3 loss increases reactive oxygen species production, resulting in enhanced HIF1a stabilization. Strikingly, SIRT3 is deleted in 40% of human breast cancers, and its loss correlates with the upregulation of HIF1a target genes. Finally, we find that SIRT3 overexpression directly represses the Warburg effect in breast cancer cells. In sum, we identify SIRT3 as a regulator of HIF1a and a suppressor of the Warburg effect. RNA isolated from brown adipose tissue of SIRT3 WT and KO mice. 5 wild-type samples and 5 SIRT3 KO samples

2011-03-15 | E-GEOD-27309 | biostudies-arrayexpress

SIRT3 opposes metabolic reprogramming of cancer cells through HIF1a destabilization

2011-03-15 | GSE27309 | GEO

USP29-mediated HIF1a stabilization promotes Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis

Project description:Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In hepatocellular carcinoma (HCC), aberrant expression of hypoxia inducible factor 1 a (HIF1a) and increased aerobic glycolysis metabolism represent drivers of the development of resistance to therapy with the multi-kinase inhibitor Sorafenib. However, it has remained unknown how HIF1a is activated and how its activity and the subsequent induction of aerobic glycolysis promotes Sorafenib resistance in HCC. Here, we report the ubiquitin-specific peptidase USP29 as a new regulator of HIF1a and of aerobic glycolysis during the development of Sorafenib resistance in HCC. In particular, we have identified USP29 as a critical deubiquitylase (DUB) of HIF1a, which directly deubiquitinates and stabilizes HIF1a and, thus, promotes its transcriptional activity. Among the transcriptional targets of HIF1a is the gene encoding for hexokinase 2 (HK2), a key enzyme of the glycolytic pathway. The absence of USP29, and thus of HIF1a transcriptional activity, reduces the levels of aerobic glycolysis and reinstalls the sensitivity to Sorafenib treatment in Sorafenib-resistant HCC cells in vitro and in xenograft transplantation mouse models in vivo. Notably, the absence of USP29 and high HK2 expression levels correlate with the response of HCC patients to Sorafenib therapy. Together, the data demonstrate that, as a DUB of HIF1a, USP29 promotes Sorafenib resistance in HCC cells by upregulating glycolysis, thereby opening new avenues for therapeutically targeting Sorafenib-resistant HCC in patients.

2021-07-27 | GSE158458 | GEO

Mus musculus

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

| PRJNA141031 | ENA

Inhibition of glycolysis in pathogenic TH17 cells through targeting a miR-21-Peli1-c-Rel pathway prevents autoimmunity

Project description:It is well known that some pathogenic cells have enhanced glycolysis, the regulatory network leading to increased glycolysis are not well characterized. Here, we show that CNS-infiltrated pathogenic TH17 cells from diseased mice specifically upregulate glycolytic pathway genes compared to homeostatic intestinal TH17 cells. Bioenergetic assay and metabolomics analyses indicate that in vitro derived pathogenic TH17 cells are highly glycolytic compared to nonpathogenic TH17 cells. Chromatin landscape analyses demonstrate TH17 cells in vivo show distinct chromatin states, and pathogenic TH17 cells show enhanced chromatin accessibility at glycolytic genes with NF-kB binding sites. Mechanistic studies reveal that miR-21 targets the E3 ubiquitin ligase Peli1-c-Rel pathway to promote glucose metabolism of pathogenic TH17 cells. Therapeutic targeting c-Rel-mediated glycolysis in pathogenic TH17 cells represses autoimmune diseases. These findings extend our understanding of the regulation TH17 cell glycolysis in vivo and provide insights for future therapeutic intervention to TH17 cell mediated autoimmune diseases.

2020-04-01 | GSE127768 | GEO

Transcriptional profile of Th17 cells: The role of glycolysis

Project description:The aim of this study is to investigate a role of glycolysis in transcriptional programing of Th17 cells during differentiation. Naïve CD4 T cells were differentiated towards Th17 cells with or without a mild inhibition of glycolysis, and transcriptome signature was analyzed. We found about 200 transcripts were differentially regulated. Further pathway analysis suggested that glycolysis controls genes associated with IL-2/STAT5 signaling during Th17 differentiation. Inhibition of glycolysis resulted in enrichment of genes associated with translational processes and Th17 signature genes.

2020-06-01 | GSE115339 | GEO

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

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

2023-01-18 | GSE207941 | GEO

Glycolysis Promotes Phosphoinositide 3-Kinase Signaling In Support of T Helper 17 Cell-Mediated Autoimmunity

Project description:T helper (Th) cell differentiation is driven by antigen and accessory signals that activate phosphoinositide 3-kinase (PI3K) to induce transcriptional and metabolic reprogramming including aerobic glycolysis (the Warburg effect). Here, we show that ATP generated through glycolysis fuels PI3K signaling to promote pathogenic Th17 cell responses. Mice with T cell-specific ablation of the glycolytic enzyme lactate dehydrogenase A (LDHA) were resistant to Th17 cell-mediated experimental autoimmune encephalomyelitis in association with defective T cell activation, migration, proliferation, and differentiation. LDHA deficiency crippled the cellular redox balance and inhibited ATP production causing attenuated phosphoinositide (3,4,5)-trisphosphate generation, and diminished activation of the Akt kinase and phosphorylation of its transcription factor target Foxo1. Th17 cell-specific expression of an Akt-insensitive Foxo1 mutant recapitulated the Th17 cell differentiation defects caused by LDHA deficiency. Thus, PI3K signaling and glycolytic bioenergetics constitute a positive feedback regulatory circuit essential for Th17 cell-mediated autoimmunity.

2021-03-27 | GSE164959 | GEO

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