Th135 - Sodium Perturbs Mitochondrial Respiration and Induces Dysfunctional Tregs

Beatriz Côrte-Real – 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; Ibrahim Hamad – 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; Ralf Linker – Department of Neurology, University of Regensburg, Regensburg, Germany; Dominik Müller – Experimental and Clinical Research Center, a joint cooperation of Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, 13125 Berlin, Germany.

Abstract Text: 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 temporary HS-encounter or ETC blockade rapidly induces a pro-inflammatory signature, leading to long-term dysfunction in vitro and in vivo. 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.