Journal article
Induction of pathogenic T(H)17 cells by inducible salt-sensing kinase SGK1
Nature (London), Vol.496(7446), pp.513-517
25/Apr/2013
PMID: 23467085
Abstract
T(H)17 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 diseases(1). IL-23 has a critical role in stabilizing and reinforcing the T(H)17 phenotype by increasing expression of IL-23 receptor (IL-23R) and endowing T(H)17 cells with pathogenic effector functions(2,3). However, the precise molecular mechanism by which IL-23 sustains the T(H)17 response and induces pathogenic effector functions has not been elucidated. Here we used transcriptional profiling of developing T(H)17 cells to construct a model of their signalling network and nominate major nodes that regulate T(H)17 development. We identified serum glucocorticoid kinase 1 (SGK1), a serine/threonine kinase(4), as an essential node downstream of IL-23 signalling. SGK1 is critical for regulating IL-23R expression and stabilizing the T(H)17 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 cells(5-8). We show here that a modest increase in salt concentration induces SGK1 expression, promotes IL-23R expression and enhances T(H)17 cell differentiation in vitro and in vivo, accelerating the development of autoimmunity. Loss of SGK1 abrogated Na+-mediated T(H)17 differentiation in an IL-23-dependent manner. These data demonstrate that SGK1 has a critical role in the induction of pathogenic T(H)17 cells and provide a molecular insight into a mechanism by which an environmental factor such as a high salt diet triggers T(H)17 development and promotes tissue inflammation.
Details
- Title
- Induction of pathogenic T(H)17 cells by inducible salt-sensing kinase SGK1
- Creators
- Chuan Wu - Brigham and Women's HospitalNir Yosef - Broad InstituteTheresa Thalhamer - Brigham and Women's HospitalChen Zhu - Brigham and Women's HospitalSheng Xiao - Brigham and Women's HospitalYasuhiro Kishi - Harvard Medical SchoolAviv Regev (Corresponding Author) - Massachusetts Institute of TechnologyVijay K. Kuchroo (Corresponding Author) - Brigham and Women's Hospital
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.496(7446), pp.513-517; 25/Apr/2013
- Number of pages
- 5
- Publisher
- Springer Nature
- Language
- English
- DOI
- https://doi.org/10.1038/nature11984
- PMID
- 23467085
- Grant note
- 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 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.
- Record Identifier
- 993429084503596
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