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

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