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ScienceShot: Salt Under Pressure
Artem R. Oganov & Weiwei Zhang

Salty Food May Be a Culprit in Autoimmune Diseases

For decades, doctors have been admonishing us to cut back on salt to reduce the odds of a heart attack or stroke. Now, there may be a new reason to avoid the seasoning: Studies on rodents and cultured cells, reported today, reveal that dietary salt might promote autoimmune diseases such as multiple sclerosis and inflammatory bowel disease.

The studies "have done a wonderful job of pushing the knowledge forward and exploring something that is potentially clinically important," says immunologist David Fox of the University of Michigan Medical School in Ann Arbor, who wasn't involved in the research. Daniel Cua, an immunologist at Merck Research Laboratories in Palo Alto, California, concurs. The work "is really well done with a lot of mechanistic understanding."

The findings suggest that salt spurs the specialization of TH17 cells. Although these immune cells protect us from harmful bacteria and fungi, they have also been implicated in illnesses such as inflammatory bowel disease, multiple sclerosis, and psoriasis. TH17 cells mature from unspecialized T cells, and, depending on their influences, they can become beneficial or destructive.

Researchers converged on the results from different directions. Immunobiologist David Hafler of the Yale School of Medicine and colleagues found that people who admitted to eating a lot of fast food harbored more TH17 cells. One ingredient that fast food contains in prodigious amounts is salt. To determine whether salt accounted for the surfeit of TH17 cells, Hafler and colleagues spiked cultures of unspecialized T cells with sodium chloride. "The results were perhaps among the most dramatic of my career as a research scientist," he says. Modestly raising salt concentrations, mimicking the levels in the tissues of an animal eating a high-salt diet, boosted the number of TH17 cells that matured in the cultures nearly 10 times. And these TH17 cells started making inflammation-provoking molecules, indicating that they'd become the harmful variety.

The scientists next tested whether this ominous effect occurred in animals. They prompted mice to develop experimental autoimmune encephalomyelitis (EAE), a neurological illness similar to multiple sclerosis that is fostered by "bad" TH17 cells. They fed some of the rodents meals that contained about as much salt as a typical Western diet. Compared with animals that lived on low-salt food, mice that munched high-salt chow developed EAE sooner and had more severe symptoms, the team reports in Nature.

Working independently from Hafler's group, computational biologist Aviv Regev of the Broad Institute in Cambridge, Massachusetts; immunologist Vijay Kuchroo of Harvard Medical School in Boston; and colleagues also hit upon a link between salt and autoimmunity. They tracked gene activity over the 3-day maturation period of a TH17 cell and revealed the molecular circuit that controls the process. One of the most influential genes in this network wasSGK1, and it has a salt connection, helping cells manage sodium levels. Using T cell cultures, the team found that salt promotes the specialization of TH17 cells through SGK1.

Sodium levels are higher in the fluids of the body's tissues, where TH17 cells battle pathogens, than in the bloodstream. TH17 cells' sensitivity to salt may be adaptive under normal conditions, ensuring that they turn on in the right place. "You don't want T cells activated in the peripheral blood," Hafler says. "You want them to be activated when they go into the tissues."

But increasing salt levels by eating a lot of salty food might mean trouble. The medical implications of the findings could be profound, notes human geneticist Judy Cho of the Yale School of Medicine, who wasn't involved in the research. For example, autoimmune diseases such as multiple sclerosis and type 1 diabetes have become more prevalent in recent decades, and "a massive increase in salt intake could easily explain this."

Researchers now need to confirm that salt is a factor in human autoimmune diseases, says immunologist John O'Shea of the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Maryland. People should not assume that the link is "a done deal" in humans. Scientists are ready to find out, Kuchroo says. "The stage is set to do precise experiments to test the hypothesis."