Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs

Beatriz F. Côrte-Real; Ibrahim Hamad; Rebeca Arroyo Hornero; Sabrina Geisberger; Joris Roels; Lauren Van Zeebroeck; Aleksandra Dyczko; Marike W. van Gisbergen; Henry Kurniawan; Allon Wagner; Nir Yosef; Susanne N.Y. Weiss; Klaus G. Schmetterer; Agnes Schröder; Luka Krampert; Stefanie Haase; Hendrik Bartolomaeus; Niels Hellings; Yvan Saeys; Ludwig J. Dubois; Dirk Brenner; Stefan Kempa; David A. Hafler; Johannes Stegbauer; Ralf A. Linker; Jonathan Jantsch; Dominik N. Müller; Markus Kleinewietfeld

doi:10.1016/j.cmet.2023.01.009

Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs

Beatriz F. Côrte-Real, Ibrahim Hamad, Rebeca Arroyo Hornero, Sabrina Geisberger, Joris Roels, Lauren Van Zeebroeck, Aleksandra Dyczko, Marike W. van Gisbergen, Henry Kurniawan, Allon Wagner, Nir Yosef, Susanne N.Y. Weiss, Klaus G. Schmetterer, Agnes Schröder, Luka Krampert, Stefanie Haase, Hendrik Bartolomaeus, Niels Hellings, Yvan Saeys, Ludwig J. DuboisDirk Brenner, Stefan Kempa, David A. Hafler, Johannes Stegbauer, Ralf A. Linker, Jonathan Jantsch, Dominik N. Müller, Markus Kleinewietfeld^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	299-315.e8
Number of pages	18
Journal	Cell Metabolism
Volume	35
Issue number	2
DOIs	https://doi.org/10.1016/j.cmet.2023.01.009
Publication status	Published - 7 Feb 2023

Keywords

autoimmunity
FOXP3
high salt
mitochondrial respiration
regulatory T cells

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Côrte-Real, B. F., Hamad, I., Arroyo Hornero, R., Geisberger, S., Roels, J., Van Zeebroeck, L., Dyczko, A., van Gisbergen, M. W., Kurniawan, H., Wagner, A., Yosef, N., Weiss, S. N. Y., Schmetterer, K. G., Schröder, A., Krampert, L., Haase, S., Bartolomaeus, H., Hellings, N., Saeys, Y., ... Kleinewietfeld, M. (2023). Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs. Cell Metabolism, 35(2), 299-315.e8. https://doi.org/10.1016/j.cmet.2023.01.009

@article{5ee861f2b6e64412aebabe638597ebac,

title = "Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs",

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 = "autoimmunity, FOXP3, high salt, mitochondrial respiration, regulatory T cells",

author = "C{\^o}rte-Real, {Beatriz F.} and Ibrahim Hamad and {Arroyo Hornero}, Rebeca and Sabrina Geisberger and Joris Roels and {Van Zeebroeck}, Lauren and Aleksandra Dyczko and {van Gisbergen}, {Marike W.} and Henry Kurniawan and Allon Wagner and Nir Yosef and Weiss, {Susanne N.Y.} and Schmetterer, {Klaus G.} and Agnes Schr{\"o}der and Luka Krampert and Stefanie Haase and Hendrik Bartolomaeus and Niels Hellings and Yvan Saeys and Dubois, {Ludwig J.} and Dirk Brenner and Stefan Kempa and Hafler, {David A.} and Johannes Stegbauer and Linker, {Ralf A.} and Jonathan Jantsch and M{\"u}ller, {Dominik N.} and Markus Kleinewietfeld",

note = "Funding Information: We thank Anneleen Geuzens, Dries Swinnen, Stefaan Dervaux, Niels Vandamme, Bart Ghesqui{\`e}re, 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 f{\"u}r 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 f{\"u}r 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 Artifici{\"e}le 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. Funding Information: We thank Anneleen Geuzens, Dries Swinnen, Stefaan Dervaux, Niels Vandamme, Bart Ghesqui{\`e}re, 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 f{\"u}r 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 f{\"u}r 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 Artifici{\"e}le 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{\textquoteright}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 . Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = feb,

day = "7",

doi = "10.1016/j.cmet.2023.01.009",

language = "English",

volume = "35",

pages = "299--315.e8",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "2",

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Côrte-Real, BF, Hamad, I, Arroyo Hornero, R, Geisberger, S, Roels, J, Van Zeebroeck, L, Dyczko, A, van Gisbergen, MW, Kurniawan, H, Wagner, A, Yosef, N, Weiss, SNY, Schmetterer, KG, Schröder, A, Krampert, L, Haase, S, Bartolomaeus, H, Hellings, N, Saeys, Y, Dubois, LJ, Brenner, D, Kempa, S, Hafler, DA, Stegbauer, J, Linker, RA, Jantsch, J, Müller, DN & Kleinewietfeld, M 2023, 'Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs', Cell Metabolism, vol. 35, no. 2, pp. 299-315.e8. https://doi.org/10.1016/j.cmet.2023.01.009

TY - JOUR

T1 - Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs

AU - Côrte-Real, Beatriz F.

AU - Hamad, Ibrahim

AU - Arroyo Hornero, Rebeca

AU - Geisberger, Sabrina

AU - Roels, Joris

AU - Van Zeebroeck, Lauren

AU - Dyczko, Aleksandra

AU - van Gisbergen, Marike W.

AU - Kurniawan, Henry

AU - Wagner, Allon

AU - Yosef, Nir

AU - Weiss, Susanne N.Y.

AU - Schmetterer, Klaus G.

AU - Schröder, Agnes

AU - Krampert, Luka

AU - Haase, Stefanie

AU - Bartolomaeus, Hendrik

AU - Hellings, Niels

AU - Saeys, Yvan

AU - Dubois, Ludwig J.

AU - Brenner, Dirk

AU - Kempa, Stefan

AU - Hafler, David A.

AU - Stegbauer, Johannes

AU - Linker, Ralf A.

AU - Jantsch, Jonathan

AU - Müller, Dominik N.

AU - Kleinewietfeld, Markus

N1 - Funding Information: 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. Funding Information: 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 . Publisher Copyright: © 2023 Elsevier Inc.

PY - 2023/2/7

Y1 - 2023/2/7

N2 - 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.

AB - 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.

KW - autoimmunity

KW - FOXP3

KW - high salt

KW - mitochondrial respiration

KW - regulatory T cells

U2 - 10.1016/j.cmet.2023.01.009

DO - 10.1016/j.cmet.2023.01.009

M3 - Article

C2 - 36754020

SN - 1550-4131

VL - 35

SP - 299-315.e8

JO - Cell Metabolism

JF - Cell Metabolism

IS - 2

ER -