Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs

Beatriz F Côrte-Real¹, Ibrahim Hamad¹, Rebeca Arroyo Hornero¹, Sabrina Geisberger², Joris Roels³, Lauren Van Zeebroeck¹, Aleksandra Dyczko¹, Marike W van Gisbergen⁴, Henry Kurniawan⁵, Allon Wagner⁶, Nir Yosef⁷, Susanne N Y Weiss⁸, Klaus G Schmetterer⁹, Agnes Schröder¹⁰, Luka Krampert⁸, Stefanie Haase¹¹, Hendrik Bartolomaeus¹², Niels Hellings¹³, Yvan Saeys¹⁴, Ludwig J Dubois⁴, Dirk Brenner¹⁵, Stefan Kempa¹⁶, David A Hafler¹⁷, Johannes Stegbauer¹⁸, Ralf A Linker¹¹, Jonathan Jantsch¹⁹, Dominik N Müller²⁰, Markus Kleinewietfeld²¹

Affiliations

¹ 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.
² 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.
³ VIB-UGent Center for Inflammation Research, 9052 Gent, Belgium; VIB BioImaging Core, 9052 Gent, Belgium.
⁴ The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Developmental Biology, Maastricht University, 6200 MD Maastricht, the Netherlands.
⁵ Experimental & Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, 4354 Esch-sur-Alzette, Luxembourg.
⁶ 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.
⁷ 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.
⁸ Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg and University of Regensburg, 93053 Regensburg, Germany.
⁹ 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.
¹⁰ Department of Orthodontics, University Hospital Regensburg, 93053 Regensburg, Germany.
¹¹ Department of Neurology, University of Regensburg, 93053 Regensburg, Germany.
¹² 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.
¹³ Department of Immunology, Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium.
¹⁴ VIB-UGent Center for Inflammation Research, 9052 Gent, Belgium.
¹⁵ 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.
¹⁶ 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.
¹⁷ Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06511, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹⁸ Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany.
¹⁹ 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.
²⁰ 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.
²¹ 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.

PMID: 36754020
DOI: 10.1016/j.cmet.2023.01.009

Free article

Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs

Beatriz F Côrte-Real et al. Cell Metab. 2023.

Free article

. 2023 Feb 7;35(2):299-315.e8.

doi: 10.1016/j.cmet.2023.01.009.

Authors

Affiliations

¹ 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.
² 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.
³ VIB-UGent Center for Inflammation Research, 9052 Gent, Belgium; VIB BioImaging Core, 9052 Gent, Belgium.
⁴ The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Developmental Biology, Maastricht University, 6200 MD Maastricht, the Netherlands.
⁵ Experimental & Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, 4354 Esch-sur-Alzette, Luxembourg.
⁶ 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.
⁷ 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.
⁸ Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg and University of Regensburg, 93053 Regensburg, Germany.
⁹ 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.
¹⁰ Department of Orthodontics, University Hospital Regensburg, 93053 Regensburg, Germany.
¹¹ Department of Neurology, University of Regensburg, 93053 Regensburg, Germany.
¹² 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.
¹³ Department of Immunology, Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium.
¹⁴ VIB-UGent Center for Inflammation Research, 9052 Gent, Belgium.
¹⁵ 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.
¹⁶ 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.
¹⁷ Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06511, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹⁸ Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany.
¹⁹ 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.
²⁰ 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.
²¹ 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.

PMID: 36754020
DOI: 10.1016/j.cmet.2023.01.009

Abstract

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.

Keywords: FOXP3; autoimmunity; high salt; mitochondrial respiration; regulatory T cells.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Comment in

Salty Treg cells get out of balance.
Papafragkos I, Verginis P. Papafragkos I, et al. Cell Metab. 2023 Feb 7;35(2):228-230. doi: 10.1016/j.cmet.2023.01.008. Cell Metab. 2023. PMID: 36754015

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Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs

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Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs

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