Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1

Transcriptional profiling of developing TH17 cells identifies serum glucocorticoid kinase 1 (SGK1) as an essential node downstream of IL-23 signalling, and transcriptional analysis shows that a modest increase in salt concentration induces SGK1 expression, promotes IL-23 receptor expression and enhances TH17 cell differentiation, accelerating the development of autoimmunity. Two independent groups have come to the same surprising conclusion: that increased salt concentrations promote autoimmune disease by stimulating the production of interleukin-17-producing helper T (TH17) cells from CD4+ T cells. Chuan Wu et al. show that increases in salt concentrations induce serum glucocorticoid kinase 1 (SGK1) in T cells and enhance TH17 differentiation in vitro and in vivo in mice. Markus Kleinewietfeld et al. find that salt induces murine and human TH17 cells by a mechanism dependent on activation of SGK1 and the p38 MAP kinase/NFAT5 pathway. Mice on a high-salt diet develop a more severe experimental autoimmune encephalomyelitis, a model for brain inflammation, owing to high numbers of infiltrating TH17 cells. These studies raise the possibility that high salt intake might trigger tissue inflammation and autoimmune disease in humans. A further paper from Nir Yosef et al. presents a global view of the gene networks regulating TH17 cell differentiation. TH17 cells (interleukin-17 (IL-17)-producing helper T cells) are highly proinflammatory cells that are critical for clearing extracellular pathogens and for inducing multiple autoimmune diseases1. IL-23 has a critical role in stabilizing and reinforcing the TH17 phenotype by increasing expression of IL-23 receptor (IL-23R) and endowing TH17 cells with pathogenic effector functions2,3. However, the precise molecular mechanism by which IL-23 sustains the TH17 response and induces pathogenic effector functions has not been elucidated. Here we used transcriptional profiling of developing TH17 cells to construct a model of their signalling network and nominate major nodes that regulate TH17 development. We identified serum glucocorticoid kinase 1 (SGK1), a serine/threonine kinase4, as an essential node downstream of IL-23 signalling. SGK1 is critical for regulating IL-23R expression and stabilizing the TH17 cell phenotype by deactivation of mouse Foxo1, a direct repressor of IL-23R expression. SGK1 has been shown to govern Na+ transport and salt (NaCl) homeostasis in other cells5,6,7,8. We show here that a modest increase in salt concentration induces SGK1 expression, promotes IL-23R expression and enhances TH17 cell differentiation in vitro and in vivo, accelerating the development of autoimmunity. Loss of SGK1 abrogated Na+-mediated TH17 differentiation in an IL-23-dependent manner. These data demonstrate that SGK1 has a critical role in the induction of pathogenic TH17 cells and provide a molecular insight into a mechanism by which an environmental factor such as a high salt diet triggers TH17 development and promotes tissue inflammation.