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

C Wu, N Yosef, T Thalhamer, C Zhu, S Xiao, Y Kishi… - Nature, 2013 - nature.com
C Wu, N Yosef, T Thalhamer, C Zhu, S Xiao, Y Kishi, A Regev, VK Kuchroo
Nature, 2013nature.com
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 …
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.
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