[en] FOXP3+ regulatory T cells (Tregs) are central for peripheral tolerance, and their deregulation is associated with autoimmunity. Dysfunctional autoimmune Tregs display pro-inflammatory features and altered mitochondrial metabolism, but contributing factors remain elusive. High salt (HS) has been identified to alter immune function and to promote autoimmunity. By investigating longitudinal transcriptional changes of human Tregs, we identified that HS induces metabolic reprogramming, recapitulating features of autoimmune Tregs. Mechanistically, extracellular HS raises intracellular Na+, perturbing mitochondrial respiration by interfering with the electron transport chain (ETC). Metabolic disturbance by a temporary HS encounter or complex III blockade rapidly induces a pro-inflammatory signature and FOXP3 downregulation, leading to long-term dysfunction in vitro and in vivo. The HS-induced effect could be reversed by inhibition of mitochondrial Na+/Ca2+ exchanger (NCLX). Our results indicate that salt could contribute to metabolic reprogramming and that short-term HS encounter perturb metabolic fitness and long-term function of human Tregs with important implications for autoimmunity.
Disciplines :
Immunology & infectious disease
Author, co-author :
Côrte-Real, Beatriz F; VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research (IRC), Hasselt University, 3590 Diepenbeek, Belgium, Department of Immunology, Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium
Hamad, Ibrahim; VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research (IRC), Hasselt University, 3590 Diepenbeek, Belgium, Department of Immunology, Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium
Arroyo Hornero, Rebeca; VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research (IRC), Hasselt University, 3590 Diepenbeek, Belgium, Department of Immunology, Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium
Geisberger, Sabrina; Experimental and Clinical Research Center, a joint cooperation of Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, 13125 Berlin, Germany, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Integrative Proteomics and Metabolomics, 13125 Berlin, Germany, DZHK (German Centre for Cardiovascular Research), partner site Berlin, 10785 Berlin, Germany, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
Roels, Joris; VIB-UGent Center for Inflammation Research, 9052 Gent, Belgium, VIB BioImaging Core, 9052 Gent, Belgium
Van Zeebroeck, Lauren; VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research (IRC), Hasselt University, 3590 Diepenbeek, Belgium, Department of Immunology, Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium
Dyczko, Aleksandra; VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research (IRC), Hasselt University, 3590 Diepenbeek, Belgium, Department of Immunology, Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium
van Gisbergen, Marike W; The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Developmental Biology, Maastricht University, 6200 MD Maastricht, the Netherlands
KURNIAWAN, Henry ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology ; Experimental & Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, 4354 Esch-sur-Alzette, Luxembourg
Wagner, Allon; Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA 94720, USA, Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA
Yosef, Nir; Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA 94720, USA, Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA, Chan Zuckerberg Biohub Investigator, San Francisco, CA 94158, USA, Ragon Institute of Massachusetts General Hospital, MIT and Harvard University, Cambridge, MA 02139, USA, Department of Systems Immunology, Weizmann Institute of Science, 7610001 Rehovot, Israel
Weiss, Susanne N Y; Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg and University of Regensburg, 93053 Regensburg, Germany
Schmetterer, Klaus G; Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg and University of Regensburg, 93053 Regensburg, Germany, Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria
Schröder, Agnes; Department of Orthodontics, University Hospital Regensburg, 93053 Regensburg, Germany
Krampert, Luka; Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg and University of Regensburg, 93053 Regensburg, Germany
Haase, Stefanie; Department of Neurology, University of Regensburg, 93053 Regensburg, Germany
Bartolomaeus, Hendrik; Experimental and Clinical Research Center, a joint cooperation of Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, 13125 Berlin, Germany, DZHK (German Centre for Cardiovascular Research), partner site Berlin, 10785 Berlin, Germany
Hellings, Niels; Department of Immunology, Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium
Saeys, Yvan; VIB-UGent Center for Inflammation Research, 9052 Gent, Belgium
Dubois, Ludwig J; The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Developmental Biology, Maastricht University, 6200 MD Maastricht, the Netherlands
BRENNER, Dirk ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Immunology and Genetics ; Experimental & Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, 4354 Esch-sur-Alzette, Luxembourg, Odense Research Center for Anaphylaxis (ORCA), Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, 5230 Odense, Denmark
Kempa, Stefan; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Integrative Proteomics and Metabolomics, 13125 Berlin, Germany
Hafler, David A; Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06511, USA, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Stegbauer, Johannes; Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany
Linker, Ralf A; Department of Neurology, University of Regensburg, 93053 Regensburg, Germany
Jantsch, Jonathan; Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg and University of Regensburg, 93053 Regensburg, Germany, Institute for Medical Microbiology, Immunology, and Hygiene, University Hospital Cologne and Faculty of Medicine, University of Cologne, 50935 Cologne, Germany
Müller, Dominik N; Experimental and Clinical Research Center, a joint cooperation of Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, 13125 Berlin, Germany, DZHK (German Centre for Cardiovascular Research), partner site Berlin, 10785 Berlin, Germany, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany
Kleinewietfeld, Markus ; VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research (IRC), Hasselt University, 3590 Diepenbeek, Belgium, Department of Immunology, Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium. Electronic address: markus.kleinewietfeld@uhasselt.vib.be
We thank Anneleen Geuzens, Dries Swinnen, Stefaan Dervaux, Niels Vandamme, Bart Ghesquière, Camila Takeno Cologna, Riet de Rycke, Saskia Lippens, Thomas Bartolomaeus, and Anja Maehler for technical assistance and support. S.G. was supported by the Bundesministerium für Bildung und Forschung (BMBF) funding MSTARS. J.J. received funding from the DFG (German Research Foundation, JA1993/6-1) and SFB 1350 grant (387509280, TPB5). D.N.M. and H.B. were supported by the DFG (394046635– SFB 1365); D.N.M. was also supported by the DFG (SFB-1470 - A06) and by the Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK, 81Z0100106). J.S. was supported by the DFG (STE2042/2-1), D.B. and H.K. were supported by the FNR-ATTRACT program (A14/BM/7632103), and D.B. by FNR-CORE grant (C18/BM/12691266) of the Luxembourg National Research Fund. Y.S. and J.R. were supported by the Flemish Government under the “Onderzoeksprogramma Artificiële Intelligentie (AI) Vlaanderen” program. D.A.H received funding from the National Institutes of Health (NIH) (U19 AI089992, R25 NS079193, P01 AI073748, U24 AI11867, R01 AI22220, UM 1HG009390, P01 AI039671, P50 CA121974, and R01 CA227473) and the National Multiple Sclerosis Society (NMSS, CA1061-A-18 and RG-1802-30153). M.K. was supported by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (640116); by a SALK-grant from the government of Flanders; by an Odysseus-grant (G0G1216FWO) and senior research project (G080121N) of the Research Foundation Flanders, Belgium (FWO); and by a BOF grant (ADMIRE, 21GP17BOF) from Hasselt University. B.F.C.R. and I.H. designed and performed most experiments and analyzed and interpreted the data. R.A.H, L.V.Z. S.G. A.D. H.K. S.N.Y.W. K.G.S. A.S. J.J. S.H. L.K. and H.B. performed experiments and analyzed data. J.R. and Y.S. performed analysis on tEM micrographs and interpreted data. M.V.G and L.D. assisted with Seahorse experiments and interpreted data. A.W. N.Y. N.H. R.L. D.B. J.S. S.K. and D.A.H. gave conceptual input. D.N.M. supervised experiments and interpreted data. M.K. led and conceived the project, supervised experiments, and interpreted data. B.F.C.R, I.H. and M.K. wrote the manuscript with key editing by S.G. and D.N.M. and further input from all authors. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research.We thank Anneleen Geuzens, Dries Swinnen, Stefaan Dervaux, Niels Vandamme, Bart Ghesquière, Camila Takeno Cologna, Riet de Rycke, Saskia Lippens, Thomas Bartolomaeus, and Anja Maehler for technical assistance and support. S.G. was supported by the Bundesministerium für Bildung und Forschung (BMBF) funding MSTARS. J.J. received funding from the DFG ( German Research Foundation , JA1993/6-1 ) and SFB 1350 grant ( 387509280 , TPB5). D.N.M. and H.B. were supported by the DFG ( 394046635 – SFB 1365); D.N.M. was also supported by the DFG ( SFB-1470 - A06 ) and by the Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK, 81Z0100106 ). J.S. was supported by the DFG (STE2042/2-1), D.B. and H.K. were supported by the FNR -ATTRACT program ( A14/BM/7632103 ), and D.B. by FNR -CORE grant ( C18/BM/12691266 ) of the Luxembourg National Research Fund. Y.S. and J.R. were supported by the Flemish Government under the “Onderzoeksprogramma Artificiële Intelligentie (AI) Vlaanderen” program. D.A.H received funding from the National Institutes of Health (NIH) ( U19 AI089992 , R25 NS079193 , P01 AI073748 , U24 AI11867 , R01 AI22220 , UM 1HG009390 , P01 AI039671 , P50 CA121974 , and R01 CA227473 ) and the National Multiple Sclerosis Society (NMSS, CA1061-A-18 and RG-1802-30153 ). M.K. was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program ( 640116 ); by a SALK -grant from the government of Flanders; by an Odysseus -grant ( G0G1216FWO ) and senior research project ( G080121N ) of the Research Foundation Flanders , Belgium (FWO); and by a BOF grant (ADMIRE, 21GP17BOF ) from Hasselt University .
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