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

Nature. 2013 Apr 25;496(7446):513-7. doi: 10.1038/nature11984. Epub 2013 Mar 6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects*
  • Encephalomyelitis, Autoimmune, Experimental / chemically induced
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / metabolism
  • HEK293 Cells
  • Humans
  • Immediate-Early Proteins / deficiency
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / immunology
  • Interleukin-17 / biosynthesis
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism*
  • Mice
  • Phenotype
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptors, Interleukin / biosynthesis
  • Receptors, Interleukin / immunology
  • Sodium Chloride / pharmacology*
  • Sodium Chloride, Dietary / pharmacology
  • Th17 Cells / drug effects*
  • Th17 Cells / enzymology
  • Th17 Cells / immunology
  • Th17 Cells / pathology*

Substances

  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Immediate-Early Proteins
  • Interleukin-17
  • Receptors, Interleukin
  • Sodium Chloride, Dietary
  • interleukin-23 receptor, mouse
  • Sodium Chloride
  • Interferon-gamma
  • Protein-Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase

Associated data

  • GEO/GSE43956
  • GEO/GSE43957
  • GEO/GSE43969