Letter | Published:

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

Nature volume 496, pages 513517 (25 April 2013) | Download Citation



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.

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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.


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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

    • Chuan Wu
    • , Nir Yosef
    •  & Theresa Thalhamer

    These authors contributed equally to this study.

    • Theresa Thalhamer

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


  1. Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, 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, Massachusetts 02142, USA

    • Nir Yosef
    • , Aviv Regev
    •  & Vijay K. Kuchroo
  3. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02140, USA

    • Aviv Regev


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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Aviv Regev or Vijay K. Kuchroo.

Supplementary information

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  1. 1.

    Supplementary information

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

Excel files

  1. 1.

    Supplementary Table 1

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

  2. 2.

    Supplementary Table 2

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

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