Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature volume 496, pages 513–517 (2013)Cite this article

Subjects

Abstract

TH17 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 diseases1. IL-23 has a critical role in stabilizing and reinforcing the TH17 phenotype by increasing expression of IL-23 receptor (IL-23R) and endowing TH17 cells with pathogenic effector functions2,3. However, the precise molecular mechanism by which IL-23 sustains the 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 signalling network and nominate major nodes that regulate TH17 development. We identified serum glucocorticoid kinase 1 (SGK1), a serine/threonine kinase4, as an essential node downstream of IL-23 signalling. SGK1 is critical for regulating IL-23R expression and stabilizing the TH17 cell phenotype by deactivation of mouse Foxo1, a direct repressor of IL-23R expression. SGK1 has been shown to govern Na+ transport and salt (NaCl) homeostasis in other cells5,6,7,8. We show here 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 SGK1 has a critical role in the induction of pathogenic TH17 cells and provide a molecular insight into a mechanism by which an environmental factor such as a high salt diet triggers TH17 development and promotes tissue inflammation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: SGK1 is specifically induced in T H 17 cells and is important for their maintenance.
Figure 2: SGK1-deficient mice are resistant to EAE, owing to a defect in maintaining the T H 17 phenotype.
Figure 3: SGK1 signalling promotes IL-23R expression through phosphorylation of Foxo1.
Figure 4: NaCl potentiates T H 17 cell differentiation in vitro and in vivo, enhancing EAE induction.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

The microarray data sets have been deposited in the Gene Expression Omnibus database under accession numbers GSE43956, GSE43957 and GSE43969.

References

  1. Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V. K. IL-17 and Th17 Cells. Annu. Rev. Immunol. 27, 485–517 (2009)

    Article  CAS  Google Scholar 

  2. Aggarwal, S., Ghilardi, N., Xie, M. H., de Sauvage, F. J. & Gurney, A. L. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J. Biol. Chem. 278, 1910–1914 (2003)

    Article  CAS  Google Scholar 

  3. Zhou, L. et al. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nature Immunol. 8, 967–974 (2007)

    Article  CAS  Google Scholar 

  4. Lang, F. et al. (Patho)physiological significance of the serum- and glucocorticoid-inducible kinase isoforms. Physiol. Rev. 86, 1151–1178 (2006)

    Article  CAS  Google Scholar 

  5. Wulff, P. et al. Impaired renal Na+ retention in the sgk1-knockout mouse. J. Clin. Invest. 110, 1263–1268 (2002)

    Article  CAS  Google Scholar 

  6. Salker, M. S. et al. Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure. Nature Med. 17, 1509–1513 (2011)

    Article  CAS  Google Scholar 

  7. Zhang, L., Cui, R., Cheng, X. & Du, J. Antiapoptotic effect of serum and glucocorticoid-inducible protein kinase is mediated by novel mechanism activating IκB kinase. Cancer Res. 65, 457–464 (2005)

    CAS  PubMed  Google Scholar 

  8. Shelly, C. & Herrera, R. Activation of SGK1 by HGF, Rac1 and integrin-mediated cell adhesion in MDCK cells: PI-3K-dependent and -independent pathways. J. Cell Sci. 115, 1985–1993 (2002)

    CAS  PubMed  Google Scholar 

  9. Yosef, N. et al. ANAT: a tool for constructing and analyzing functional protein networks. Sci. Signal. 4, pl1 (2011)

    Article  Google Scholar 

  10. Brunet, A. et al. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol. Cell. Biol. 21, 952–965 (2001)

    Article  CAS  Google Scholar 

  11. Wei, G. et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30, 155–167 (2009)

    Article  Google Scholar 

  12. Di Pietro, N. et al. Serum- and glucocorticoid-inducible kinase 1 (SGK1) regulates adipocyte differentiation via forkhead box O1. Mol. Endocrinol. 24, 370–380 (2010)

    Article  CAS  Google Scholar 

  13. Essaghir, A., Dif, N., Marbehant, C. Y., Coffer, P. J. & Demoulin, J. B. The transcription of FOXO genes is stimulated by FOXO3 and repressed by growth factors. J. Biol. Chem. 284, 10334–10342 (2009)

    Article  CAS  Google Scholar 

  14. Ciofani, M. et al. A validated regulatory network for Th17 cell specification. Cell 151, 289–303 (2012)

    Article  CAS  Google Scholar 

  15. Berer, K. et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 538–541 (2011)

    Article  ADS  CAS  Google Scholar 

  16. Sczesnak, A. et al. The genome of th17 cell-inducing segmented filamentous bacteria reveals extensive auxotrophy and adaptations to the intestinal environment. Cell Host Microbe 10, 260–272 (2011)

    Article  CAS  Google Scholar 

  17. Stegbauer, J. et al. Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system. Proc. Natl Acad. Sci. USA 106, 14942–14947 (2009)

    Article  ADS  CAS  Google Scholar 

  18. Herrada, A. A. et al. Aldosterone promotes autoimmune damage by enhancing Th17-mediated immunity. J. Immunol. 184, 191–202 (2010)

    Article  CAS  Google Scholar 

  19. Diakov, A. & Korbmacher, C. A novel pathway of epithelial sodium channel activation involves a serum- and glucocorticoid-inducible kinase consensus motif in the C terminus of the channel's alpha-subunit. J. Biol. Chem. 279, 38134–38142 (2004)

    Article  CAS  Google Scholar 

  20. Loffing, J. et al. Aldosterone induces rapid apical translocation of ENaC in early portion of renal collecting system: possible role of SGK. Am. J. Physiol. Renal Physiol. 280, F675–F682 (2001)

    Article  CAS  Google Scholar 

  21. Reich, M. et al. GenePattern 2.0. Nature Genet. 38, 500–501 (2006)

    Article  CAS  Google Scholar 

  22. Storey, J. D., Xiao, W., Leek, J. T., Tompkins, R. G. & Davis, R. W. Significance analysis of time course microarray experiments. Proc. Natl Acad. Sci. USA 102, 12837–12842 (2005)

    Article  ADS  CAS  Google Scholar 

  23. Chechik, G. & Koller, D. Timing of gene expression responses to environmental changes. J. Comput. Biol. 16, 279–290 (2009)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank D. Kozoriz for cell sorting and A. Waisman for providing Il17fCre mice. L. Zhou, D. Accili, J. Demoulin and K. Sato provided reagents. This work was supported by the US National Institutes of Health (NS030843, NS045937, AI073748 and AI045757 to V.K.K.; 1P01HG005062-01, 1P50HG006193-01 and DP1-OD003958-01 to A.R.; and K01DK090105 to S.X.); the National MS Society (RG2571 to V.K.K.); the Howard Hughes Medical Institute (A.R.); the Klarman Cell Observatory; Guthy Jackson Foundation; and the Austrian Science Fund (FWF, J 3091-B12 to T.T.).

Author information

Author notes

  1. Theresa Thalhamer

    Present address: Present address: Department of Molecular Biology, University of Salzburg, Hellbrunnerstrasse 34, 5020 Salzburg, Austria.,

  2. Chuan Wu, Nir Yosef and Theresa Thalhamer: These authors contributed equally to this study.

Authors and Affiliations

  1. Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Chuan Wu, Nir Yosef, Theresa Thalhamer, Chen Zhu, Sheng Xiao, Yasuhiro Kishi & Vijay K. Kuchroo

  2. Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Nir Yosef, Aviv Regev & Vijay K. Kuchroo

  3. Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, 02140, Massachusetts, USA

    Aviv Regev

Authors
  1. Chuan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nir Yosef
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Theresa Thalhamer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chen Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sheng Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yasuhiro Kishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aviv Regev
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Vijay K. Kuchroo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Author Contributions C.W, N.Y. and T.T. carried out experiments and wrote the manuscript. C.Z., S.X. and Y.K. carried out experiments. N.Y. analysed the data. A.R. and V.K.K. supervised the study and edited the manuscript.

Corresponding authors

Correspondence to Aviv Regev or Vijay K. Kuchroo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

This file contains Supplementary Figures 1-8, legends for Supplementary Tables 1-2 (see separate excel files), Supplementary Methods and additional references. (PDF 6814 kb)

Supplementary Table 1

This file contains the candidate selection in the Il23r–/– and Sgk1–/– data sets (see Supplementary Information file for full legend). (XLSX 62 kb)

Supplementary Table 2

The file contains the microarray data analysis (see Supplementary Information file for full legend). (XLSX 356 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, C., Yosef, N., Thalhamer, T. et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496, 513–517 (2013). https://doi.org/10.1038/nature11984

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11984

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing