ArrayExpress Uploader0mouseWTWTSgk1-/-Sgk1-/-7157arrayexpress_sid6Th17 cells are highly proinflammatory cells that are critical for clearing extracellular pathogens like fungal infections and for...E-GEOD-43956/profile/8773/arrayexpressuploader14cellcell phenotypeserineserumthreonineDec.12, 2014Falseinduction-of-pathogenic-th17-cells-by-salt-inducibE-GEOD-43956_A-AFFY-45Induction of pathogenic Th17 cells by salt inducible kinase SGK-1 (SGK-1 KO)Nov.12, 2014Th17 cells are highly proinflammatory cells that are critical for clearing extracellular pathogens like fungal infections and for induction of multiple autoimmune diseases1. IL-23 plays a critical role in stabilizing and endowing Th17 cells with pathogenic effector functions2. Previous studies have shown that IL-23 signaling reinforces the Th17 phenotype by increasing expression of IL-23 receptor (IL-23R)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 unbiased transcriptional profiling of developing Th17 cells to construct a model of their signaling network and identify major nodes that regulate Th17 development. We identified serum glucocorticoid kinase-1 (SGK1), as an essential node downstream of IL-23 signaling, critical for regulating IL-23R expression and for stabilizing the Th17 cell phenotype by deactivation of Foxo1, a direct repressor of IL-23R expression. A serine-threonine kinase homologous to AKT4, SGK1 has been associated with cell cycle and apoptosis, and has been shown to govern Na+ transport and homeostasis5, 6 7, 8. We here show that a modest increase in salt (NaCl) concentration induces SGK1 expression, promotes IL-23R expression and enhances Th17 cell differentiation in vitro and in vivo, ultimately accelerating the development of autoimmunity. The loss of SGK1 resulted in abrogation of Na+-mediated Th17 differentiation in an IL-23-dependent manner. These data indicate that SGK1 is a critical regulator for the induction of pathogenic Th17 cells and provides a molecular insight by which an environmental factor such as a high salt diet could trigger Th17 development and promote tissue inflammation. Th17 cells; comparing Sgk1-/- to WThttp://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-43956http://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-43956/samples/