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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2013-03-06

AUTHORS

Chuan Wu, Nir Yosef, Theresa Thalhamer, Chen Zhu, Sheng Xiao, Yasuhiro Kishi, Aviv Regev, Vijay K. Kuchroo

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. More... »

PAGES

513

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nature11984

DOI

http://dx.doi.org/10.1038/nature11984

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1050969377

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/23467085


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