High salt disrupts anti-inflammatory immune cells’ energy production
In cell cultures, salt inhibited Treg cells' ability to suppress other immune cells activity
Eating too much salt can disrupt the energy metabolism of regulatory T-cells (Tregs), which normally work to control inflammation and fight autoimmunity, prompting them to adopt an inflammatory profile similar to what’s seen in multiple sclerosis (MS) and other autoimmune diseases, a study found.
Even a short-term exposure to salt rendered Tregs less effective at controlling disease in a mouse model of MS. Inhibiting a molecule called NCLX, which helps cells’ energy production centers (mitochondria) take up salt, restored the Tregs’ ability to control disease, however.
“The better understanding of factors and underlying molecular mechanisms contributing to Treg dysfunction in autoimmunity is an important question in the field,” said Markus Kleinewietfeld, PhD, the study’s senior author and a professor at the VIB Center for Inflammation Research and Hasselt University, Belgium, in a press release from the Max Delbrück Center. “The further exploration of such sodium [salt]-elicited effects may offer novel strategies for altering Treg function in different types of diseases.”
The study, “Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs,” was published in Cell Metabolism.
Tregs are immune cells that dampen the activity of other immune system components and work to control inflammation that could harm tissues if left unchecked.
Their dysfunction has been implicated in autoimmune diseases. It’s thought Tregs’ inability to suppress other immune cells may support the inflammatory environment that marks MS and other immune-related conditions.
High dietary salt intake, common in Western diets, has been shown to impact Tregs adversely, making them more pro-inflammatory. These salt-exposed Tregs are markedly similar to the abnormal Tregs seen in autoimmune conditions like MS.
That observation suggests high salt “could contribute to an overall immune imbalance,” according to the researchers, but the mechanisms behind this weren’t known.
The function of immune cells is highly dependent on metabolic processes that drive energy production. The researchers previously found that high salt disrupts mitochondrial function of other immune cell types, namely monocytes and macrophages, leading to functional changes. Disruptions in mitochondria have also been recently observed in Tregs from MS patients.
Salt intake’s effect on Treg cells
“Considering our previous findings … as well as the new observations on mitochondria in Tregs from autoimmune patients, we were wondering if sodium might elicit similar issues in Tregs of healthy volunteers,” said Dominik Müller, PhD, one of the study’s investigators and a researcher at the Max Delbrück Center and the Experimental and Clinical Research Center, Berlin.
In cell cultures, the researchers found that high salt concentrations inhibited the ability of healthy human Tregs to suppress the activity of other immune cells.
The gene activity pattern of these salt-exposed cells was also changed. Genes showing changes generally reflected a more pro-inflammatory state of the cells. Similar genes are altered in Tregs from patients with MS.
Gene activity analyses also revealed “severe changes in cellular metabolism” after salt exposure, according to researchers, with some of the most strongly affected genes associated with mitochondrial function and energy production.
A series of experiments suggested high salt led to impairments in mitochondrial respiration, the set of oxygen-dependent metabolic reactions that produce energy. This metabolic disturbance was associated with signs of Treg dysfunction, including an inflammatory profile and reduction in the activity of FOX3P, a gene critical for Treg’s activities.
In healthy human volunteers, a high-salt diet — more than 7 grams a day — was associated with reduced levels of anti-inflammatory molecules in Tregs compared with people on a low-salt diet.
To explore further, the researchers isolated Tregs from healthy mice and cultured them in either salty or normal conditions, then injected those cells into a mouse model of MS. While injection of the normal Tregs could prevent MS from developing in the animals, treatment with the salt-exposed cells couldn’t.
The findings show “even the short-term [high salt] perturbation of mitochondrial respiration could lead to long-term disruption of … Treg function,” the researchers wrote.
Mechanistically, the team found that high salt conditions in the cellular environment raised sodium levels inside the cells. A transporter called NCLX then helped sodium be taken up by mitochondria, disrupting their function.
When NCLX was inhibited, salt-induced disruptions to mitochondrial function were reversed. In the MS mouse model, administering the NCLX inhibitor restored salt-exposed Tregs’ ability to control the disease.
While inhibiting NCLX may show promise for salt-sensitive diseases, more research is needed to better understand these molecular mechanisms and clear up how they relate to disease, Kleinewietfeld said.
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