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Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions (RNA-Seq I)

ABSTRACT: Pyruvate dehydrogenase (PDH) is the central enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle. The importance of PDH function in Th17 cells is unknown. Here, we show that PDH is essential for the generation of a unique glucose-derived citrate pool needed for Th17 cell proliferation, survival and effector function. In vivo, mice harboring a T cell-specific deletion of PDH were less susceptible to developing experimental autoimmune encephalomyelitis. Mechanistically, the absence of PDH in Th17 cells increased glutaminolysis, glycolysis, and lipid uptake in an mTOR-dependent manner. However, cellular citrate remained critically low in mutant Th17 cells, which interfered with oxidative phosphorylation (OXPHOS), lipid synthesis and histone acetylation crucial for the transcription of Th17 signature genes. Increasing cellular citrate in PDH-deficient Th17 cells restored their metabolism and function, identifying a metabolic feedback loop within central carbon metabolism that may offer possibilities for therapeutically targeting Th17 cell-driven autoimmunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE222880 | GEO | 2023/03/02

REPOSITORIES: GEO

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Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions (ATAC-Seq)

Project description:Pyruvate dehydrogenase (PDH) is the central enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle. The importance of PDH function in Th17 cells is unknown. Here, we show that PDH is essential for the generation of a unique glucose-derived citrate pool needed for Th17 cell proliferation, survival and effector function. In vivo, mice harboring a T cell-specific deletion of PDH were less susceptible to developing experimental autoimmune encephalomyelitis. Mechanistically, the absence of PDH in Th17 cells increased glutaminolysis, glycolysis, and lipid uptake in an mTOR-dependent manner. However, cellular citrate remained critically low in mutant Th17 cells, which interfered with oxidative phosphorylation (OXPHOS), lipid synthesis and histone acetylation crucial for the transcription of Th17 signature genes. Increasing cellular citrate in PDH-deficient Th17 cells restored their metabolism and function, identifying a metabolic feedback loop within central carbon metabolism that may offer possibilities for therapeutically targeting Th17 cell-driven autoimmunity.

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Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions (RNA-Seq II)

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Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions

Project description:Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions

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Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions (ATAC-Seq)

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Gene expression of HUVECS treated with either siRNA to CTRL, PDHA1, or SREBF2 and treated with TNF 16 hours

Project description:The endothelium is a major target of the proinflammatory cytokine, tumor necrosis factor alpha (TNFα). Exposure of endothelial cells (EC) to proinflammatory stimuli leads to an increase in mitochondrial metabolism, however, the function and regulation of elevated mitochondrial metabolism in EC in response to pro-inflammatory cytokines remains unclear. Using high-resolution metabolomics and 13C-glucose labeled flux techniques, we demonstrate that pyruvate dehydrogenase activity (PDH) and tricarboxylic acid cycle flux is elevated in human umbilical vein ECs (HUVECs) in response to overnight (16 hrs) treatment with TNFα (10 ng/mL). Mechanistic studies indicate that TNFα mediates these metabolic changes via mitochondrial specific protein degradation of pyruvate dehydrogenase kinase 4 (PDK4, inhibitor of PDH) by the Lon protease via an NF-κB dependent mechanism. Using RNA sequencing following siRNA mediated knockdown of the catalytically active subunit of PDH, PDHE1a (PDHA1 gene), we show that PDH flux controls the transcription of approximately one-third of the genes that are upregulated by TNFa stimulation. Notably, TNFa induced PDH flux regulates a unique signature of proinflammatory mediators (cytokines and chemokines) but not inducible adhesion molecules. Using metabolomics and ChIP sequencing (H3AcK27), we demonstrate that TNFα induced PDH flux promotes histone acetylation of specific gene sets via citrate accumulation and ATP-citrate lyase activity. Together, these results indicate that targeting endothelial glucose oxidation and/or acetyl CoA generation may offer a novel therapeutic strategy in the treatment of vascular inflammation.

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Gene expression of HUVECS treated with either siRNA to CTRL or PDHA1 and treated with TNF 16 hours

Project description:The endothelium is a major target of the proinflammatory cytokine, tumor necrosis factor alpha (TNFα). Exposure of endothelial cells (EC) to proinflammatory stimulileads to an increase in mitochondrial metabolism, however, the function and regulation of elevated mitochondrial metabolism in EC in response to pro-inflammatory cytokines remains unclear. Using high-resolution metabolomics and13C-glucose labeled flux techniques, we demonstrate thatpyruvate dehydrogenase activity (PDH) and tricarboxylic acid cycle flux is elevated in human umbilical vein ECs (HUVECs) in response to overnight (16 hrs) treatment withTNFα (10 ng/mL).Mechanistic studies indicate thatTNFα mediates these metabolic changes via mitochondrial specific protein degradation of pyruvate dehydrogenase kinase 4 (PDK4, inhibitor of PDH) by the Lon protease via an NF-κB dependent mechanism. Using RNA sequencing following siRNA mediated knockdown of thecatalytically active subunit of PDH, PDHE1a(PDHA1 gene), we show that PDH fluxcontrols the transcription of approximately one-third of the genes that are upregulated by TNFastimulation. Notably, TNFainduced PDHflux regulates a unique signature of proinflammatory mediators (cytokines and chemokines) but not inducible adhesion molecules.Using metabolomics and ChIP sequencing (H3AcK27), we demonstrate that TNFα induced PDH flux promotes histone acetylation of specific gene sets via citrate accumulation and ATP-citrate lyase activity.Together, these resultsindicate that targeting endothelial glucose oxidation and/or acetyl CoA generation may offer a novel therapeutic strategy in the treatment of vascular inflammation.

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