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

Nature
Authors
Keywords
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.

Year of Publication
2013
Journal
Nature
Volume
496
Issue
7446
Pages
513-7
Date Published
2013 Apr 25
ISSN
1476-4687
URL
DOI
10.1038/nature11984
PubMed ID
23467085
PubMed Central ID
PMC3637879
Links
Grant list
R01 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