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

Abstract

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.