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

Autor:	Soriano-Baguet L; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg., Grusdat M; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg., Kurniawan H; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg., Benzarti M; Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg; Faculty of Science, Technology, and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg., Binsfeld C; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg., Ewen A; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg., Longworth J; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg., Bonetti L; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg., Guerra L; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg., Franchina DG; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg., Kobayashi T; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg., Horkova V; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg., Verschueren C; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg., Helgueta S; Luxembourg Center of Neuropathology, 3555 Dudelange, Luxembourg; Epigenetics Team, Systems Biology Group, Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg., Gérard D; Epigenetics Team, Systems Biology Group, Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg., More TH; Department of Bioinformatics and Biochemistry, Braunschweig Integrated Center of Systems Biology, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany., Henne A; Department of Bioinformatics and Biochemistry, Braunschweig Integrated Center of Systems Biology, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany., Dostert C; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg., Farinelle S; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg., Lesur A; Metabolomics Platform, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg., Gérardy JJ; Luxembourg Center of Neuropathology, 3555 Dudelange, Luxembourg; National Center of Pathology, Laboratoire National de Santé (LNS), Dudelange, Luxembourg., Jäger C; Luxembourg Center for Systems Biomedicine, University of Luxembourg, 4362 Esch-sur-Alzette, Luxembourg., Mittelbronn M; Faculty of Science, Technology, and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg; Luxembourg Center of Neuropathology, 3555 Dudelange, Luxembourg; National Center of Pathology, Laboratoire National de Santé (LNS), Dudelange, Luxembourg; Luxembourg Center for Systems Biomedicine, University of Luxembourg, 4362 Esch-sur-Alzette, Luxembourg; Department of Life Sciences and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg; Department of Cancer Research, Luxembourg Institute of Health, 1526 Luxembourg, Luxembourg., Sinkkonen L; Epigenetics Team, Systems Biology Group, Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg., Hiller K; Department of Bioinformatics and Biochemistry, Braunschweig Integrated Center of Systems Biology, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany., Meiser J; Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg; Metabolomics Platform, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg., Brenner D; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg; Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark. Electronic address: dirk.brenner@lih.lu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 Mar 28; Vol. 42 (3), pp. 112153. Date of Electronic Publication: 2023 Feb 26.
DOI:	10.1016/j.celrep.2023.112153
Abstrakt:	Pyruvate dehydrogenase (PDH) is the central enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle. The importance of PDH function in T helper 17 (Th17) cells still remains to be studied. Here, we show that PDH is essential for the generation of a glucose-derived citrate pool needed for Th17 cell proliferation, survival, and effector function. In vivo, mice harboring a T cell-specific deletion of PDH are less susceptible to developing experimental autoimmune encephalomyelitis. Mechanistically, the absence of PDH in Th17 cells increases glutaminolysis, glycolysis, and lipid uptake in a mammalian target of rapamycin (mTOR)-dependent manner. However, cellular citrate remains critically low in mutant Th17 cells, which interferes with oxidative phosphorylation (OXPHOS), lipid synthesis, and histone acetylation, crucial for transcription of Th17 signature genes. Increasing cellular citrate in PDH-deficient Th17 cells restores their metabolism and function, identifying a metabolic feedback loop within the central carbon metabolism that may offer possibilities for therapeutically targeting Th17 cell-driven autoimmunity. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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