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

Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. 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 signaling network and nominate major nodes that regulate Th17 development. We identified serum glucocorticoid kinase-1 (SGK1), a serine-threonine kinase 4 , as an essential node downstream of IL-23 signaling. SGK1 here show 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 SGK-1 plays a critical role in the induction of pathogenic Th17 cells and provides a molecular insight into a mechanism by which an environmental factor such as a high salt diet triggers Th17 development and promotes tissue inflammation. To determine the molecular mechanisms by which naïve T cells develop into effector Th17 cells, we measured genome-wide mRNA expression profiles using microarrays along 18 time points over 72 hours following the in vitro exposure of naive T cells to Th17 polarizing conditions (TGF-1 with IL-6). To examine the role of IL-23 in Th17 development, we added IL-23 at the late time points (48 – 72 h) and monitored the transcriptional response in both wild-type (WT) and Il23r –/– cells. We ranked the genes according to their extent of induction in cells treated with TGF-1 and IL-6 (relative to nonpolarized activated T cells) and repression in Il23r –/– cells (relative to WT cells) (Methods; Fig. 1a and Supplementary Table 1). SGK1 was one of the top ranking genes, whose transcriptional regulation is strongly associated with both IL-23R signaling and Th17 cell differentiation (Fig. 1a). qPCR analysis showed that SGK1 is induced at low levels by TGF-1 (iTreg), and not induced in other T cell subsets (Th0, Th1, Th2). As expected, it is most highly expressed under Th17 differentiation conditions (Fig. 1b). SGK1 expression is strongly induced during the first two hours following stimulation of naïve T cells under Th17-polarizing conditions. This is followed …