Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1
Author(s)Wu, Chuan; Yosef, Nir; Thalhamer, Theresa; Zhu, Chen; Xiao, Sheng; Kishi, Yasuhiro; Regev, Aviv; Kuchroo, Vijay K.; ... Show more Show less
Induction of pathogenic T[subscript H]17 cells by inducible salt-sensing kinase SGK1
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T[subscript H]17 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 T[subscript H]17 phenotype by increasing expression of IL-23 receptor (IL-23R) and endowing T[subscript H]17 cells with pathogenic effector functions. However, the precise molecular mechanism by which IL-23 sustains the T[subscript H]17 response and induces pathogenic effector functions has not been elucidated. Here we used transcriptional profiling of developing T[subscript H]17 cells to construct a model of their signalling network and nominate major nodes that regulate T[subscript H]17 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 T[subscript H]17 cell phenotype by deactivation of mouse Foxo1, a direct repressor of IL-23R expression. SGK1 has been shown to govern Na[superscript +] 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 T[subscript H]17 cell differentiation in vitro and in vivo, accelerating the development of autoimmunity. Loss of SGK1 abrogated Na[superscript +]-mediated T[subscript H]17 differentiation in an IL-23-dependent manner. These data demonstrate that SGK1 has a critical role in the induction of pathogenic T[subscript H]17 cells and provide a molecular insight into a mechanism by which an environmental factor such as a high salt diet triggers T[subscript H]17 development and promotes tissue inflammation.
Departmentmove to dc.description.sponsorship; Massachusetts Institute of Technology. Department of Biology
Nature Publishing Group
Wu, Chuan, Nir Yosef, Theresa Thalhamer, Chen Zhu, Sheng Xiao, Yasuhiro Kishi, Aviv Regev, and Vijay K. Kuchroo. “Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1.” Nature 496, no. 7446 (March 6, 2013): 513-517.
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