Salt develops a taste for Th17 lymphocytes

Helper T lymphocytes that make the hormone interleukin-17 (IL-17), called Th17 cells, contribute to inflammation and autoimmune diseases (review). The development of Th17 cells was known to require IL-23 but it was not known exactly why.  To gain some perspective, the authors measured gene transcripts found in Th17 cells as they develop over time from naïve mouse T lymphocytes treated with transforming growth factor-beta (TGFb) and IL-6.  They found that SGK1, an enzyme that phosphorylates proteins and has been shown to regulate sodium (Na+) transport and salt (NaCl) balance in other cells, was induced nearly 200-fold.  They emphasize that IL-23 is “critical” to the induction and maintenance of SGK1 but much of that evidence is relegated to the supplement data.  “Network analysis” with a computer program strengthened their suspicion that SGK1 is a “node” in the IL-23 signaling pathway.  

Mice without SGK1 (SGK1-knockouts, KO) have fewer Th17 cells that make less IL-17 when treated with IL-23; notably SGK1 deficiency also alters genes regulating other T cell subsets, including interferon-gamma (Ifng), Tbx21, and Gata3 (see also the previous gloss on transcription factors regulating Th17).  To test the role of SGK1, they immunized “floxed” SGK1 (conditional KO) mice with a myelin protein (MOG), which induces in some mouse strains a multiple sclerosis (MS) like disease called experimental autoimmune encephalitis (EAE).  EAE severity was significantly reduced in mice without SGK1 in Th17 cells or CD4+ helper T cells,  (fig 2a, KO score <1 normal="" vs.="">3), which corresponded with a greatly reduced number of Th17 cells in the organ targeted by this autoimmune disease, the central nervous system (CNS).  They also saw that CNS-infiltrating cells in EAE had expressed IL-17 at one time (eYFP+, fig 2e) but that expression of IL-17 by CD4 cells was lost in SGK1-KO animals (eYFP+ IL17-), suggesting that SGK1 was required to maintain expression.

That was nice but now the spice – could dietary salt modulate immunity through SGK1?    Indeed, they found that a high salt diet (HSD) accelerates the development of EAE in normal mice (fig 4e, top 2 lines, trend line offset to the left is HSD) while it does nothing to the GSK1-KO animals (lower, lines).  And connecting at least one of the dots between diet and Th17, they found that HSD also increased more than 2-fold Th17 cells and to a lesser degree interferon-gamma expressing cells in the CNS,  and the induction depended on SGK1 (fig 5f, shown, Th17 left, IFNg right; open bars SGK1-CD4-KO).  A companion paper pursued the role of dietary salt in EAE   

Nature. 2013 Apr 25;496(7446):513-7.  Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1.  Wu C, Yosef N, Thalhamer T, Zhu C, Xiao S, Kishi Y, Regev A, Kuchroo VK.