Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs

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

doi:10.1016/j.cmet.2023.01.009

Cited by 33 publications

(17 citation statements)

References 73 publications

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“…Our results showing the enhanced cellular metabolism of NaCl-conditioned CD8 + T cells are in stark contrast to the recently reported perturbation of mitochondrial respiration in Treg cells upon exposure to high NaCl concentrations (Corte-Real et al, 2023). While CD8 + T cells generated increased ATP via engagement of multiple layers of cellular metabolism, high NaCl was reported to decrease the metabolic fitness (Macintyre et al, 2014) of Treg cells through inhibitory effects on mitochondrial respiration (Corte-Real et al, 2023). As a consequence, Treg cells lose their suppressive functions and acquire the ability to produce proinflammatory cytokines such as IFN-.…”

Section: Discussioncontrasting

confidence: 99%

“…This finding argues for a direct mechanistic link between NaCl-sensing and glucose metabolism. Additionally, experimental differences, such as short versus sustained NaCl exposure in Treg and CD8 + T cells, respectively, could account for the differential impact of NaCl on these different cells (Corte-Real et al, 2023;Pearce et al, 2013). Notably, both the loss of Treg suppressive functions and the potentiation of CD8 + T cell cytotoxicity, are known to jointly contribute to improved tumor elimination (Shan et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…Elevated sodium ion (Na + ) concentration was demonstrated to strongly promote the differentiation of Th17 cells under polarizing conditions and to promote the upregulation of self-regulatory cytokines in these cells upon restimulation (Matthias et al, 2020; Wu et al, 2013) (Kleinewietfeld et al, 2013). Recently, Na + ions were also shown to abrogate the immunosuppressive function of Treg cells through perturbation of mitochondrial respiration (Corte-Real et al, 2023; Hernandez et al, 2015). Mitochondrial Na + influx via the Na + /Ca 2+ exchanger (NCLX) blocked complex II/III of the electron transport chain, leading to decreased oxidative phosphorylation and thus decreased ATP production (Corte-Real et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, Na + ions were also shown to abrogate the immunosuppressive function of Treg cells through perturbation of mitochondrial respiration (Corte-Real et al, 2023; Hernandez et al, 2015). Mitochondrial Na + influx via the Na + /Ca 2+ exchanger (NCLX) blocked complex II/III of the electron transport chain, leading to decreased oxidative phosphorylation and thus decreased ATP production (Corte-Real et al, 2023). Additionally, Na + ions promoted Th2 cell responses, presumably through mTORC2 signaling, which has implications for the pathogenesis of allergic diseases (Matthias et al, 2019b).…”

Section: Introductionmentioning

confidence: 99%

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Sodium chloride in the tumor microenvironment enhances T-cell metabolic fitness and cytotoxicity

Soll,

Arunkumar,

Alissa-Alkhalaf

et al. 2023

Preprint

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Adoptive T-cell therapy has become a powerful weapon for cancer treatment. The efficacy of antitumor immunity is associated with the metabolic state of cytotoxic T cells, which is highly sensitive to the tumor microenvironment. It is therefore of considerable interest to bypass immunosuppressive signals in the tumor microenvironment and to identify factors that augment cytotoxic effector functions and ultimately tumor killing. Whether ionic signals serve as aberrant immune signals and influence the adaptive human antitumor immune response is still largely unexplored. We therefore investigated the effect of sodium on the phenotype, function and metabolic regulation of human CD8+ T cells using transcriptomic, metabolomic, high-dimensional flow cytometric and functional assays. We demonstrate a significant enrichment of sodium in solid tumors from patients with breast cancer, which leaves a transcriptomic imprint on intratumoral immune cells. Sodium chloride (NaCl) enhanced the activation state and effector functions of human CD8+ memory T cells. These functional alterations were associated with enhanced metabolic fitness, particularly increases in glycolysis, oxidative phosphorylation and overall nutrient uptake. These NaCl-induced effects translated into increased tumor cell killing in vitro and in a tumor mouse model in vivo. We therefore propose NaCl as a positive regulator of acute antitumor immunity that could be harnessed for ex vivo conditioning of adoptively transferred T cells, such as CAR T-cells.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sodium chloride in the tumor microenvironment enhances T-cell metabolic fitness and cytotoxicity

Soll,

Arunkumar,

Alissa-Alkhalaf

et al. 2023

Preprint

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“…It is generally recognized that extrinsic elements could elicit impactful effects, with diet as one of the main contributing factors in affecting the gut microbiota composition and function [ 1 , 2 , 21 ]. Western dietary components, such as high-salt intake, are known to have a negative impact on host homeostasis by affecting the immune system and altering the gut microbiota and disease [ 18 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. In murine gut microbiota, high-salt diet (HSD) is associated with reduction of health-promoting bacteria notoriously known as producer of short-chain fatty acids (SCFA) such as Lactobacillus spp., Bifidobacterium , Blautia and Faecalibaculum [ 28 , 29 , 38 , 39 , 40 , 41 ], alongside an increase in the abundance of Akkermansia , another opportunistic SCFA-producer that has been shown to affect host immunity and disease in different model systems [ 42 , 43 ].…”

Section: Introductionmentioning

confidence: 99%

Impact of High Salt-Intake on a Natural Gut Ecosystem in Wildling Mice

et al. 2023

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The mammalian holobiont harbors a complex and interdependent mutualistic gut bacterial community. Shifts in the composition of this bacterial consortium are known to be a key element in host health, immunity and disease. Among many others, dietary habits are impactful drivers for a potential disruption of the bacteria–host mutualistic interaction. In this context, we previously demonstrated that a high-salt diet (HSD) leads to a dysbiotic condition of murine gut microbiota, characterized by a decrease or depletion of well-known health-promoting gut bacteria. However, due to a controlled and sanitized environment, conventional laboratory mice (CLM) possess a less diverse gut microbiota compared to wild mice, leading to poor translational outcome for gut microbiome studies, since a reduced gut microbiota diversity could fail to depict the complex interdependent networks of the microbiome. Here, we evaluated the HSD effect on gut microbiota in CLM in comparison to wildling mice, which harbor a natural gut ecosystem more closely mimicking the situation in humans. Mice were treated with either control food or HSD and gut microbiota were profiled using amplicon-based methods targeting the 16S ribosomal gene. In line with previous findings, our results revealed that HSD induced significant loss of alpha diversity and extensive modulation of gut microbiota composition in CLM, characterized by the decrease in potentially beneficial bacteria from Firmicutes phylum such as the genera Lactobacillus, Roseburia, Tuzzerella, Anaerovorax and increase in Akkermansia and Parasutterella. However, HSD-treated wildling mice did not show the same changes in terms of alpha diversity and loss of Firmicutes bacteria as CLM, and more generally, wildlings exhibited only minor shifts in the gut microbiota composition upon HSD. In line with this, 16S-based functional analysis suggested only major shifts of gut microbiota ecological functions in CLM compared to wildling mice upon HSD. Our findings indicate that richer and wild-derived gut microbiota is more resistant to dietary interventions such as HSD, compared to gut microbiota of CLM, which may have important implications for future translational microbiome research.

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Selective targeting or reprogramming of intra-tumoral Tregs

Mortezaee

2024

Med Oncol

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Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs

Cited by 33 publications

References 73 publications

Sodium chloride in the tumor microenvironment enhances T-cell metabolic fitness and cytotoxicity

Sodium chloride in the tumor microenvironment enhances T-cell metabolic fitness and cytotoxicity

Impact of High Salt-Intake on a Natural Gut Ecosystem in Wildling Mice

Selective targeting or reprogramming of intra-tumoral Tregs

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