Th17 cells are highly proinflammatory cells that are critical for clearing extracellular pathogens and induction of multiple autoimmune diseases. IL-23 plays a critical role in stabilizing and endowing Th17 cells with pathogenic effector functions. IL-23 has been shown to reinforce the Th17 phenotype by increasing expression of IL-23 receptor (IL-23R). However, the molecular mechanism by which IL-23 sustains the Th17 response and induces pathogenic effector functions is unclear. Here we used unbiased transcriptional profiling of developing Th17 cells to construct a model of their signaling network and identify major nodes that regulate Th17 development. We identified serum glucocorticoid kinase-1 (SGK1) is critical for regulating IL-23R expression and for stabilizing the Th17 cell by deactivation of Foxo1, a direct repressor of IL-23R expression. SGK1 has been shown to govern Na+ transport and homeostasis. We show that a modest increase in salt (NaCl) concentration induces SGK1 expression, promotes IL-23R expression and enhances Th17 cell differentiation in vitro and in vivo, ultimately accelerating the development of autoimmunity. The loss of SGK1 resulted in abrogation of Na+-mediated Th17 differentiation in an IL-23-dependent manner. These data indicate that SGK1 is critical for the induction of pathogenic Th17 cells and provides a molecular insight by which an environmental factor such as a high salt diet could trigger Th17 development and promote tissue inflammation.
- Copyright © 2013 by The American Association of Immunologists, Inc.