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Nature DOI:10.1038/nature11984

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

Publication TypeJournal Article
Year of Publication2013
AuthorsWu, C, Yosef, N, Thalhamer, T, Zhu, C, Xiao, S, Kishi, Y, Regev, A, Kuchroo, VK
JournalNature
Volume496
Issue7446
Pages513-7
Date Published2013 Apr 25
ISSN1476-4687
KeywordsAnimals, Cell Differentiation, Encephalomyelitis, Autoimmune, Experimental, Forkhead Box Protein O1, Forkhead Transcription Factors, HEK293 Cells, Humans, Immediate-Early Proteins, Interferon-gamma, Interleukin-17, Mice, Phenotype, Phosphorylation, Protein-Serine-Threonine Kinases, Receptors, Interleukin, Sodium Chloride, Sodium Chloride, Dietary, Th17 Cells
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.

URLhttp://dx.doi.org/10.1038/nature11984
DOI10.1038/nature11984
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23467085?dopt=Abstract

Alternate JournalNature
PubMed ID23467085
PubMed Central IDPMC3637879
Grant ListR01 NS030843 / NS / NINDS NIH HHS / United States
NS030843 / NS / NINDS NIH HHS / United States
AI045757 / AI / NIAID NIH HHS / United States
DP1-OD003958-01 / OD / NIH HHS / United States
R01 NS045937 / NS / NINDS NIH HHS / United States
1P01HG005062-01 / HG / NHGRI NIH HHS / United States
K01 DK090105 / DK / NIDDK NIH HHS / United States
K01DK090105 / DK / NIDDK NIH HHS / United States
DP1 CA174427 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R37 NS030843 / NS / NINDS NIH HHS / United States
P50 HG006193 / HG / NHGRI NIH HHS / United States
AI073748 / AI / NIAID NIH HHS / United States
P01 AI045757 / AI / NIAID NIH HHS / United States
1P50HG006193-01 / HG / NHGRI NIH HHS / United States
NS045937 / NS / NINDS NIH HHS / United States
P01 AI073748 / AI / NIAID NIH HHS / United States
R29 NS030843 / NS / NINDS NIH HHS / United States
P01 HG005062 / HG / NHGRI NIH HHS / United States
DP1 OD003958 / OD / NIH HHS / United States