Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs

Tools

Item Type:	Article
Title:	Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs
Creators Name:	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., Dubois, L.J., Brenner, D., Kempa, S., Hafler, D.A., Stegbauer, J., Linker, R.A., Jantsch, J., Müller, D.N. and Kleinewietfeld, M.
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(+)/Ca(2+) 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:	Regulatory T Cells, High Salt, Mitochondrial Respiration, Autoimmunity, FOXP3
Source:	Cell Metabolism
ISSN:	1550-4131
Publisher:	Cell Press
Volume:	35
Number:	2
Page Range:	299-315
Date:	7 February 2023
Additional Information:	Copyright © 2023 Elsevier Inc. Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Public License (CC BY-NC-ND 4.0)
Official Publication:	https://doi.org/10.1016/j.cmet.2023.01.009
External Fulltext:	View full text on external repository or document server
PubMed:	View item in PubMed

Repository Staff Only: item control page