Glutamate-Cysteine Ligase; Glutathione; Animals; B-Lymphocytes; Glutathione/metabolism; Mice; Oxidation-Reduction; Lymphoid Tissue/metabolism; Lymphoid Tissue; Chemistry (all); Biochemistry, Genetics and Molecular Biology (all); Physics and Astronomy (all); General Physics and Astronomy; General Biochemistry, Genetics and Molecular Biology; General Chemistry; Multidisciplinary
Abstract :
[en] The metabolic principles underlying the differences between follicular and marginal zone B cells (FoB and MZB, respectively) are not well understood. Here we show, by studying mice with B cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that glutathione synthesis affects homeostasis and differentiation of MZB to a larger extent than FoB, while glutathione-dependent redox control contributes to the metabolic dependencies of FoB. Specifically, Gclc ablation in FoB induces metabolic features of wild-type MZB such as increased ATP levels, glucose metabolism, mTOR activation, and protein synthesis. Furthermore, Gclc-deficient FoB have a block in the mitochondrial electron transport chain (ETC) due to diminished complex I and II activity and thereby accumulate the tricarboxylic acid cycle metabolite succinate. Finally, Gclc deficiency hampers FoB activation and antibody responses in vitro and in vivo, and induces susceptibility to viral infections. Our results thus suggest that Gclc is required to ensure the development of MZB, the mitochondrial ETC integrity in FoB, and the efficacy of antiviral humoral immunity.
Disciplines :
Immunology & infectious disease
Author, co-author :
Franchina, Davide G ; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Kurniawan, Henry; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Grusdat, Melanie; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Binsfeld, Carole; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Guerra, Luana; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Bonetti, Lynn; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Soriano-Baguet, Leticia ; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Ewen, Anouk; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Kobayashi, Takumi ; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Farinelle, Sophie; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Minafra, Anna Rita; Department of Molecular Medicine II, Medical Faculty, Heinrich-Heine-University, 40225, Düsseldorf, Germany
Vandamme, Niels; National Data Mining and Modelling for Biomedicine, VIB Center for Inflammation Research, Ghent, Belgium ; Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium
Carpentier, Anaïs; National Center of Pathology (NCP), Laboratoire National de Santé (LNS), Dudelange, Luxembourg
Borgmann, Felix K; National Center of Pathology (NCP), Laboratoire National de Santé (LNS), Dudelange, Luxembourg ; Luxembourg Center of Neuropathology (LCNP), Dudelange, L-3555, Luxembourg
Jäger, Christian ; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg
Chen, Ying; Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
Kleinewietfeld, Markus; VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research (IRC) Hasselt University, Diepenbeek, Belgium ; Department of Immunology, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
Vasiliou, Vasilis ; Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA
Mittelbronn, Michel; National Center of Pathology (NCP), Laboratoire National de Santé (LNS), Dudelange, Luxembourg ; Luxembourg Center of Neuropathology (LCNP), Dudelange, L-3555, Luxembourg ; Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg ; Department of Life Sciences and Medicine (DLSM), University of Luxembourg, Esch-sur-Alzette, Luxembourg ; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, L-4362, Luxembourg ; Department of Oncology (DONC), Luxembourg Institute of Health (LIH), Luxembourg, L-1526, Dudelange, Luxembourg
Hiller, Karsten ; Department for Bioinformatics and Biochemistry, Braunschweig Integrated Center of Systems Biology (BRICS), Technische Universität Braunschweig, Rebenring 56, 38106, Braunschweig, Germany
Lang, Philipp A ; Department of Molecular Medicine II, Medical Faculty, Heinrich-Heine-University, 40225, Düsseldorf, Germany
BRENNER, Dirk ; University of Luxembourg ; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg. dirk.brenner@lih.lu ; Odense Research Center for Anaphylaxis (ORCA), Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark. dirk.brenner@lih.lu
We would like to thank Hans-Martin Jäck (FAU) and Elisabeth Letellier (Uni.Lu) for constructive feedback and continuous support; Vitaly Pozdeev (Uni.Lu), Dominique Revets (LIH), Thomas Cerutti (LIH), and Gert Van Isterdael (VIB) for tissue section microscopy and FACS sorting; the Metabolomics Platform of the LCSB (Uni.Lu); Samantha Storn (LIH) and Anaïs Oudin (LIH) and the Luxembourg Institute of Health’s Animal Welfare Structure; Charlène Verschueren (LIH) and Catherine Dostert (LIH) for assistance. D.B. is supported by the FNR-ATTRACT (A14/BM/7632103) and the FNR-CORE (C21/BM/15796788) programs. D.B., L.B., L.G., and A.E. are funded by FNR-PRIDE (PRIDE/11012546/NEXTIMMUNE), and D.B., A.E. by (PRIDE17/11823097/MicrOH). D.B. and D.G.F. are supported by FNR-RIKEN (TregBar/11228353). V.V. holds grant NIH/NIAAA (5R24AA022057). D.B and K.H. are supported by binational FNR/DFG program: the FNR-CORE grant (C18/BM/12691266) and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) project HI1400/3-1. M.K. was supported by a SALK-grant from the government of Flanders and by an Odysseus-grant of the Research Foundation Flanders, Belgium (FWO). P.A.L. is supported by the DFG (SFB974, GRK1949) and the Jürgen Manchot Foundation (MOI). M.M. would like to thank the Luxembourg National Research Fund (FNR) for the support (FNR PEARL P16/BM/11192868 grant). The authors would like to thank the Roger de Spoelberch Foundation for funding the electron microscopy platform (LCSB/LNS).We would like to thank Hans-Martin J?ck (FAU) and Elisabeth Letellier (Uni.Lu) for constructive feedback and continuous support; Vitaly Pozdeev (Uni.Lu), Dominique Revets (LIH), Thomas Cerutti (LIH), and Gert Van Isterdael (VIB) for tissue section microscopy and FACS sorting; the Metabolomics Platform of the LCSB (Uni.Lu); Samantha Storn (LIH) and Ana?s Oudin (LIH) and the Luxembourg Institute of Health?s Animal Welfare Structure; Charl?ne Verschueren (LIH) and Catherine Dostert (LIH) for assistance. D.B. is supported by the?FNR-ATTRACT (A14/BM/7632103)?and the FNR-CORE (C21/BM/15796788) programs. D.B., L.B., L.G., and A.E. are funded by FNR-PRIDE (PRIDE/11012546/NEXTIMMUNE), and D.B., A.E. by (PRIDE17/11823097/MicrOH). D.B. and D.G.F. are supported by FNR-RIKEN (TregBar/11228353). V.V. holds grant NIH/NIAAA (5R24AA022057). D.B and K.H. are supported by binational FNR/DFG program: the FNR-CORE grant (C18/BM/12691266) and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) project HI1400/3-1. M.K. was supported by a SALK-grant from the government of Flanders and by an Odysseus-grant of the Research Foundation Flanders, Belgium (FWO). P.A.L. is supported by the DFG (SFB974, GRK1949) and the J?rgen Manchot Foundation (MOI). M.M. would like to thank the Luxembourg National Research Fund (FNR) for the support (FNR PEARL P16/BM/11192868 grant). The authors would like to thank the Roger de Spoelberch Foundation for funding the electron microscopy platform (LCSB/LNS).
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