title: Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1.
abstract: 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 diseases. 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 functions. 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 kinase, 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 cells. 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.
authors: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Chuan
authors: C
authors: Wu
authors: Nir
authors: N
authors: Yosef
authors: Theresa
authors: T
authors: Thalhamer
authors: Chen
authors: C
authors: Zhu
authors: Sheng
authors: S
authors: Xiao
authors: Yasuhiro
authors: Y
authors: Kishi
authors: Aviv
authors: A
authors: Regev
authors: Vijay K
authors: VK
authors: Kuchroo
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000276:immunology; D012965:Sodium Chloride / Q000494:pharmacology*; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D058504:Th17 Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D017874:Immediate-Early Proteins; D007371:Interferon-gamma; D020381:Interleukin-17; D017346:Protein Serine-Threonine Kinases; D018123:Receptors, Interleukin; D012965:Sodium Chloride; D017673:Sodium Chloride, Dietary; D000099184:Serum-Glucocorticoid Regulated Kinases; C467200:Foxo1 protein, mouse; C528688:interleukin-23 receptor, mouse