Th17 cells are interleukin (IL) 17–producing helper cells that are a key component in the induction of multiple autoimmune diseases. Th17 cells are stabilized and given pathogenic effector functions by the presence of IL-23. A new study finds that serum glucocorticoid kinase I (SGK1) plays a critical role in this process. SGK1, an enzyme located primarily in the gut and kidney, regulates sodium absorption and sodium balance.
Chuan Wu, PhD of Harvard Medical School in Boston, and colleagues recently reported the results of their microarray data analysis online on in Nature.1 The authors performed transcriptional profiling of developing Th17 cells in order to characterize their signaling network and identify the major nodes that regulate Th17 development. They combined the microarray data with large-scale protein–protein interaction (PPI) network analysis and experimental data from several different knockout mice. They wove the data together to establish IL-23R–SGK1-Foxo1 as a critical axis for stabilizing Th17 cells.
Functionally, the authors found that if they increased salt, they were able to induce SGK1 and increase the number of Th17 cells. This was true both in vitro as well as in vivo.
They and colleagues at Yale also found that mice that were placed on a high salt diet became more susceptible to an autoimmune model of multiple sclerosis (experimental autoimmune encephalomyelitis; EAE). This increase in severity was very much reduced in SGK1-deficient mice. The results suggest that a high salt diet may be a risk factor for inflammation. The data are consistent with recent studies that demonstrated that diet and gut microbiota can have a strong effect on the frequency of effector T cells in the gut.
“I was very surprised … We never went out looking for salt-sensing molecules,” explains Vijay K. Kuchroo, DVM, PhD, also of Harvard Medical School and senior author of the study. He elaborates that the results “build an interesting hypothesis … but careful clinical trials have to be done in humans.”
Dr. Kuchroo points out that the study was one of a series of three papers published back to back in Nature. The first study identified 39 regulatory factors involved in Th17 development and highlighted drug targets that might be useful for controlling Th17 cell differentiation. The second paper (discussed above) described the role of SGK1. The third paper detailed how mice fed a high-salt diet develop more severe EAE with peripherally induced antigen-specific Th17 cells.
Markus Kleinewietfeld, PhD, of Yale School of Medicine in New Haven, Conn., and colleagues conclude in the third paper that the data justify clinical trials of dietary salt restriction in patients with multiple sclerosis and psoriasis, both of which have strong Th17 components.
