The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming

Sophia M. Hochrein; Hao Wu; Miriam Eckstein; Laura Arrigoni; Josip S. Herman; Fabian Schumacher; Christian Gerecke; Mathias Rosenfeldt; Dominic Grün; Burkhard Kleuser; Georg Gasteiger; Wolfgang Kastenmüller; Bart Ghesquière; Jan Van den Bossche; E. Dale Abel; Martin Vaeth

doi:10.1016/j.cmet.2022.02.015

The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming

Sophia M. Hochrein, Hao Wu, Miriam Eckstein, Laura Arrigoni, Josip S. Herman, Fabian Schumacher, Christian Gerecke, Mathias Rosenfeldt, Dominic Grün, Burkhard Kleuser, Georg Gasteiger, Wolfgang Kastenmüller, Bart Ghesquière, Jan Van den Bossche, E. Dale Abel, Martin Vaeth^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Experimentelle Dermatologie

194 Zitate (Scopus)

Abstract

Metabolic reprogramming is a hallmark of activated T cells. The switch from oxidative phosphorylation to aerobic glycolysis provides energy and intermediary metabolites for the biosynthesis of macromolecules to support clonal expansion and effector function. Here, we show that glycolytic reprogramming additionally controls inflammatory gene expression via epigenetic remodeling. We found that the glucose transporter GLUT3 is essential for the effector functions of Th17 cells in models of autoimmune colitis and encephalomyelitis. At the molecular level, we show that GLUT3-dependent glucose uptake controls a metabolic-transcriptional circuit that regulates the pathogenicity of Th17 cells. Metabolomic, epigenetic, and transcriptomic analyses linked GLUT3 to mitochondrial glucose oxidation and ACLY-dependent acetyl-CoA generation as a rate-limiting step in the epigenetic regulation of inflammatory gene expression. Our findings are also important from a translational perspective because inhibiting GLUT3-dependent acetyl-CoA generation is a promising metabolic checkpoint to mitigate Th17-cell-mediated inflammatory diseases.

Originalsprache	Englisch
Zeitschrift	Cell Metabolism
Jahrgang	34
Ausgabenummer	4
Seiten (von - bis)	516-532.e11
ISSN	1550-4131
DOIs	https://doi.org/10.1016/j.cmet.2022.02.015
Publikationsstatus	Veröffentlicht - 05.04.2022

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We thank Kathryn E. Wellen (University of Pennsylvania, USA), Elisabeth Sock (University of Erlangen, Germany), Alma Zernecke-Madsen, Friederike Berberich-Siebelt, Niklas Beyersdorf, and Kristen Rak (all University of Würzburg, Germany) for providing Acly fl/fl , Ppp3r1 fl/fl , Hif1af l/fl , Irf4 fl/fl , Cd28 −/− , and Stat3 fl/fl mice, respectively. SorA was kindly provided by Rolf Müller (Helmholtz Center for Infection Research, Germany). This work was supported by the Deutsche Forschungsgemeinschaft (DFG) SFB-TR 124/3 2013 , project 210879364 , SFB-TR 338/1 2021 , project 452881907 , SFB 1526/1 2022 , project 454193335 , SFB 1525/1 2022 , project 453989101 , and project grant VA882/2-1 (to M.V.); NIH U54 HL112311 (to E.D.A.); and the Interdisciplinary Center for Clinical Research (IZKF, supporting the Core Units FACS and SysMed). We would like to thank Camila Takeno Cologna, Wesley Vermaelen, Anton Willems (VIB Metabolomics Expertise Center), Sheyda Hajiesmaeili, Thorsten Bischler, and Christian Linden (IZKF Würzburg) for excellent technical assistance. We thank Kathryn E. Wellen (University of Pennsylvania, USA), Elisabeth Sock (University of Erlangen, Germany), Alma Zernecke-Madsen, Friederike Berberich-Siebelt, Niklas Beyersdorf, and Kristen Rak (all University of W?rzburg, Germany) for providing Aclyfl/fl, Ppp3r1fl/fl, Hif1afl/fl, Irf4fl/fl, Cd28?/?, and Stat3fl/fl mice, respectively. SorA was kindly provided by Rolf M?ller (Helmholtz Center for Infection Research, Germany). This work was supported by the Deutsche Forschungsgemeinschaft (DFG) SFB-TR 124/3 2013, project 210879364, SFB-TR 338/1 2021, project 452881907, SFB 1526/1 2022, project 454193335, SFB 1525/1 2022, project 453989101, and project grant VA882/2-1 (to M.V.); NIH U54 HL112311 (to E.D.A.); and the Interdisciplinary Center for Clinical Research (IZKF, supporting the Core Units FACS and SysMed). We would like to thank Camila Takeno Cologna, Wesley Vermaelen, Anton Willems (VIB Metabolomics Expertise Center), Sheyda Hajiesmaeili, Thorsten Bischler, and Christian Linden (IZKF W?rzburg) for excellent technical assistance. Conceptualization, M.V. S.M.H. B.G. W.K. G.G. D.G. J.V.d.B. B.K. and E.D.A.; experiments, S.M.H. H.W. M.E. M.V. F.S. C.G. L.A. J.S.H. and M.R.; data analysis, M.V. S.M.H. F.S. J.S.H. and B.G.; writing, M.V. The authors declare no competing interests.

Dokumente

10.1016/j.cmet.2022.02.015

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Link to publication in Scopus

SFB 1526, PANTAU: Pathomechanismen Antikörpervermittelter Autoimmunerkrankungen
Sadik, C. (Sprecher*in), Zillikens, D. (Sprecher*in), Scheffold, A. (Projektleiter*in (PI)), Schmidt, E. (Projektleiter*in (PI)), Heine, G. (Projektleiter*in (PI)), Manz, R. (Projektleiter*in (PI)), Köhl, J. (Projektleiter*in (PI)), Ludwig, R. (Projektleiter*in (PI)), Peipp, M. (Projektleiter*in (PI)), Hammers, M. C. (Projektleiter*in (PI)), Verschoor, A. (Projektleiter*in (PI)), Karsten, C. (Projektleiter*in (PI)), Nimmerjahn, F. (Projektleiter*in (PI)), Hutloff, A. (Projektleiter*in (PI)), Ibrahim, S. (Projektleiter*in (PI)), Wettschureck, N. (Projektleiter*in (PI)), Bieber, K. (Projektleiter*in (PI)), Schilf, P. (Projektleiter*in (PI)), Vaeth, M. (Projektleiter*in (PI)), Hirose, M. (Projektleiter*in (PI)), Vaeth, M. (Projektleiter*in (PI)), Baines, J. F. (Projektleiter*in (PI)), Bacher, P. (Projektleiter*in (PI)), Hoffmann, M. (Projektleiter*in (PI)), Busch, H. S. (Projektleiter*in (PI)), Höppner, M. (Projektleiter*in (PI)), Becker, M. (Projektleiter*in (PI)), Holtsche, M. M. (Projektleiter*in (PI)), Fähnrich, A. (Projektleiter*in (PI)), Szymczak, S. (Projektleiter*in (PI)), Murthy, S. (Projektleiter*in (PI)) & Lux, A. (Projektleiter*in (PI))
01.01.22 → …
Projekt: DFG Verbundprojekte › DFG Sonderforschungsbereiche / Transregios (SFB/TR)

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Hochrein, S. M., Wu, H., Eckstein, M., Arrigoni, L., Herman, J. S., Schumacher, F., Gerecke, C., Rosenfeldt, M., Grün, D., Kleuser, B., Gasteiger, G., Kastenmüller, W., Ghesquière, B., Van den Bossche, J., Abel, E. D., & Vaeth, M. (2022). The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming. Cell Metabolism, 34(4), 516-532.e11. https://doi.org/10.1016/j.cmet.2022.02.015

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title = "The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming",

abstract = "Metabolic reprogramming is a hallmark of activated T cells. The switch from oxidative phosphorylation to aerobic glycolysis provides energy and intermediary metabolites for the biosynthesis of macromolecules to support clonal expansion and effector function. Here, we show that glycolytic reprogramming additionally controls inflammatory gene expression via epigenetic remodeling. We found that the glucose transporter GLUT3 is essential for the effector functions of Th17 cells in models of autoimmune colitis and encephalomyelitis. At the molecular level, we show that GLUT3-dependent glucose uptake controls a metabolic-transcriptional circuit that regulates the pathogenicity of Th17 cells. Metabolomic, epigenetic, and transcriptomic analyses linked GLUT3 to mitochondrial glucose oxidation and ACLY-dependent acetyl-CoA generation as a rate-limiting step in the epigenetic regulation of inflammatory gene expression. Our findings are also important from a translational perspective because inhibiting GLUT3-dependent acetyl-CoA generation is a promising metabolic checkpoint to mitigate Th17-cell-mediated inflammatory diseases.",

author = "Hochrein, \{Sophia M.\} and Hao Wu and Miriam Eckstein and Laura Arrigoni and Herman, \{Josip S.\} and Fabian Schumacher and Christian Gerecke and Mathias Rosenfeldt and Dominic Gr{\"u}n and Burkhard Kleuser and Georg Gasteiger and Wolfgang Kastenm{\"u}ller and Bart Ghesqui{\`e}re and \{Van den Bossche\}, Jan and Abel, \{E. Dale\} and Martin Vaeth",

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month = apr,

day = "5",

doi = "10.1016/j.cmet.2022.02.015",

language = "English",

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Hochrein, SM, Wu, H, Eckstein, M, Arrigoni, L, Herman, JS, Schumacher, F, Gerecke, C, Rosenfeldt, M, Grün, D, Kleuser, B, Gasteiger, G, Kastenmüller, W, Ghesquière, B, Van den Bossche, J, Abel, ED & Vaeth, M 2022, 'The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming', Cell Metabolism, Jg. 34, Nr. 4, S. 516-532.e11. https://doi.org/10.1016/j.cmet.2022.02.015

TY - JOUR

T1 - The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming

AU - Hochrein, Sophia M.

AU - Wu, Hao

AU - Eckstein, Miriam

AU - Arrigoni, Laura

AU - Herman, Josip S.

AU - Schumacher, Fabian

AU - Gerecke, Christian

AU - Rosenfeldt, Mathias

AU - Grün, Dominic

AU - Kleuser, Burkhard

AU - Gasteiger, Georg

AU - Kastenmüller, Wolfgang

AU - Ghesquière, Bart

AU - Van den Bossche, Jan

AU - Abel, E. Dale

AU - Vaeth, Martin

PY - 2022/4/5

Y1 - 2022/4/5

N2 - Metabolic reprogramming is a hallmark of activated T cells. The switch from oxidative phosphorylation to aerobic glycolysis provides energy and intermediary metabolites for the biosynthesis of macromolecules to support clonal expansion and effector function. Here, we show that glycolytic reprogramming additionally controls inflammatory gene expression via epigenetic remodeling. We found that the glucose transporter GLUT3 is essential for the effector functions of Th17 cells in models of autoimmune colitis and encephalomyelitis. At the molecular level, we show that GLUT3-dependent glucose uptake controls a metabolic-transcriptional circuit that regulates the pathogenicity of Th17 cells. Metabolomic, epigenetic, and transcriptomic analyses linked GLUT3 to mitochondrial glucose oxidation and ACLY-dependent acetyl-CoA generation as a rate-limiting step in the epigenetic regulation of inflammatory gene expression. Our findings are also important from a translational perspective because inhibiting GLUT3-dependent acetyl-CoA generation is a promising metabolic checkpoint to mitigate Th17-cell-mediated inflammatory diseases.

AB - Metabolic reprogramming is a hallmark of activated T cells. The switch from oxidative phosphorylation to aerobic glycolysis provides energy and intermediary metabolites for the biosynthesis of macromolecules to support clonal expansion and effector function. Here, we show that glycolytic reprogramming additionally controls inflammatory gene expression via epigenetic remodeling. We found that the glucose transporter GLUT3 is essential for the effector functions of Th17 cells in models of autoimmune colitis and encephalomyelitis. At the molecular level, we show that GLUT3-dependent glucose uptake controls a metabolic-transcriptional circuit that regulates the pathogenicity of Th17 cells. Metabolomic, epigenetic, and transcriptomic analyses linked GLUT3 to mitochondrial glucose oxidation and ACLY-dependent acetyl-CoA generation as a rate-limiting step in the epigenetic regulation of inflammatory gene expression. Our findings are also important from a translational perspective because inhibiting GLUT3-dependent acetyl-CoA generation is a promising metabolic checkpoint to mitigate Th17-cell-mediated inflammatory diseases.

UR - https://www.scopus.com/pages/publications/85127242397

U2 - 10.1016/j.cmet.2022.02.015

DO - 10.1016/j.cmet.2022.02.015

M3 - Journal articles

C2 - 35316657

AN - SCOPUS:85127242397

SN - 1550-4131

VL - 34

SP - 516-532.e11

JO - Cell Metabolism

JF - Cell Metabolism

IS - 4

ER -

The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming

Abstract

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SFB 1526, PANTAU: Pathomechanismen Antikörpervermittelter Autoimmunerkrankungen

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