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Sci. Signal., 30 April 2013
Vol. 6, Issue 273, p. ec97
[DOI: 10.1126/scisignal.2004284]

EDITORS' CHOICE

Immunology Exacerbating Autoimmune Disease with Salt

Annalisa M. VanHook

Science Signaling, AAAS, Washington, DC 20005, USA

In addition to contributing to the immune response against pathogens, helper T (TH ) cells that produce the cytokine interleukin-17 (IL-17) also contribute to autoimmune diseases. Maintenance of both normal and pathogenic TH17 cell activities depends on activation of the IL-23 receptor (IL-23R). By performing transcriptional profiling and network analysis of transcriptional changes in wild-type and Il23r–/– mouse T cells that were activated and induced to differentiate into TH17 cells, Wu et al. identified serum glucocorticoid kinase 1 (Sgk1) as a key node downstream of IL-23R. In vitro differentiation of naïve T cells from Sgk1–/– mice revealed that SGK1 was not required for primary TH17 cell differentiation but was required for maintenance of TH17 cells and continued signaling through IL-23R. Analysis of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, in Sgk1–/– animals showed that these mice had reduced incidence of disease, severity of symptoms, and production of IL-17 compared with EAE in wild-type animals. In vitro experiments were consistent with a model in which SGK1 phosphorylates the transcription factor Foxo1 to repress its ability to indirectly activate Il23r expression. SGK1 mediates sodium (Na+) homeostasis by modulating the activity of epithelial Na+ channels, so the authors tested the effect of Na+ on TH17 cell differentiation. Increasing the concentration of NaCl in the culture medium increased expression of Sgk1, Il23r, Il17, and other genes associated with TH17 differentiation in wild-type, but not Sgk1–/–, T cells that had been activated but not treated with factors to influence their development into a particular type of TH cell. Compared with a normal diet, a high-salt diet increased the number of TH17 cells in the guts of wild-type mice but induced a milder increase in the abundance of TH17 cells in Sgk1–/– mice. In the EAE model, mice on a high-salt diet showed increased severity of disease compared with those fed a normal diet. However, a high-salt diet had a much milder effect on disease symptoms in Sgk1–/– mice. In a related study, Kleinewietfeld et al. differentiated naïve human T cells in culture conditions that mimicked the interstitial fluid of animals fed a high-salt diet and found that the additional NaCl promoted differentiation of TH17 cells that expressed markers consistent with autoimmune activity. Further experiments indicated that this effect was mediated by the kinase p38, the transcription factor and p38 target NFAT5, and the NFAT5 target Sgk1. In vivo experiments performed in this study were consistent with those reported by Wu et al. These studies suggest that production of the pathogenic TH17 cells that contribute to autoimmunity may be exacerbated by dietary salt. Commentary by O’Shea and Jones considers the implications and limitations of these findings in the context of autoimmune disease.

C. Wu, N. Yosef, T. Thalhamer, C. Zhu, S. Xiao, Y. Kishi, A. Regev, V. K. Kuchroo, Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496, 513–517 (2013). [PubMed]

M. Kleinewietfeld, A. Manzel, J. Titze, H. Kvakan, N. Yosef, R. A. Linker, D. N. Muller, D. A. Hafler, Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496, 518–522 (2013). [PubMed]

J. J. O’Shea, R. G. Jones, Rubbing salt in the wound. Nature 496, 437–439 (2013). [PubMed]

Citation: A. M. VanHook, Exacerbating Autoimmune Disease with Salt. Sci. Signal. 6, ec97 (2013).



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