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Title: | Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs | Authors: | FERNANDES CORTE-REAL, Beatriz HAMAD, Ibrahim ARROYO HORNERO, Rebeca Geisberger, Sabrina Roels, Joris VAN ZEEBROECK, Lauren DYCZKO, Aleksandra van Gisbergen, Marike W. Kurniawan, Henry Wagner, Allon Yoset, Nir Weiss, Susanne N. Y. Schmetterer, Klaus G. Schroeder, Agnes Krampert, Luka Haase, Stefanie Bartolomaeus, Hendrik HELLINGS, Niels Saeys, Yvan Dubois, Ludwig J. Brenner, Dirk Kempa, Stefan Hafler, David A. Stegbauer, Johannes Linker, Ralf A. Jantsch, Jonathan Mueller, Dominik N. KLEINEWIETFELD, Markus |
Issue Date: | 2023 | Publisher: | CELL PRESS | Source: | Cell Metabolism, 35 (2) , p. 299 - 315 | 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 mito-chondrial metabolism, but contributing factors remain elusive. High salt (HS) has been identified to alter im-mune 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. | Notes: | Kleinewietfeld, M (corresponding author), Hasselt Univ, VIB Ctr Inflammat Res IRC, VIB Lab Translat Immunomodulat, B-3590 Diepenbeek, Belgium.; Kleinewietfeld, M (corresponding author), Hasselt Univ, Biomed Res Inst, Dept Immunol, B-3590 Diepenbeek, Belgium. markus.kleinewietfeld@uhasselt.vib.be |
Keywords: | FOXP3;autoimmunity;high salt;mitochondrial respiration;regulatory T cells;Humans;Autoimmunity;Forkhead Transcription Factors;Sodium;T-Lymphocytes, Regulatory | Document URI: | http://hdl.handle.net/1942/40896 | ISSN: | 1550-4131 | e-ISSN: | 1932-7420 | DOI: | 10.1016/j.cmet.2023.01.009 | ISI #: | 001041611700001 | Rights: | 2023 Elsevier Inc. | Category: | A1 | Type: | Journal Contribution |
Appears in Collections: | Research publications |
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Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs.pdf Restricted Access | Published version | 4.94 MB | Adobe PDF | View/Open Request a copy |
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