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Wu C, Yosef N, Thalhamer T, et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1

1] Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [2].
Nature (Impact Factor: 42.35). 03/2013; 496(7446). DOI: 10.1038/nature11984
Source: PubMed

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 diseases. 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 functions. 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 kinase, 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 cells. 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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    • "IL-17A (in the literature often referred to as IL-17) was first described in 1993 [14] in human peripheral blood, as an important proinflammatory cytokine with a critical role against extracellular microorganisms and in the pathogenesis of different autoimmune diseases. Sodium chloride via the salt sensing kinase SGK1 promotes Th17 cell differentiation and autoimmunity [15] [16]. Within the IL-17 family, IL-17A and IL-17F are central players in the adaptive immune response, particularly against bacteria and fungi [17] [18] while the function of IL-17B, IL-17C and IL-17D is less understood [18]. "
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    ABSTRACT: Interleukin 17 (IL-17) includes several cytokines among which IL-17A is considered as one of the major pro-inflammatory cytokine being central to the innate and adaptive immune responses. IL-17 is produced by unconventional T cells, members of innate lymphoid cells (ILCs), mast cells, as well as typical innate immune cells, such as neutrophils and macrophages located in the epithelial barriers and characterised by a rapid response to infectious agents by recruiting neutrophils as first line of defence and inducing the production of antimicrobial peptides. Th17 responses appear pivotal in chronic and acute infections by bacteria, parasites, and fungi, as well as in autoimmune and chronic inflammatory diseases, including rheumatoid arthritis, psoriasis, and psoriatic arthritis. The data discussed in this review cumulatively indicate that innate-derived IL-17 constitutes a major element in the altered immune response against self antigens or the perpetuation of inflammation, particularly at mucosal sites. New drugs targeting the IL17 pathway include brodalumab, ixekizumab, and secukinumab and their use in psoriatic disease is expected to dramatically impact our approach to this systemic condition. Copyright © 2015 Elsevier Ltd. All rights reserved.
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    • "Mediated by the osmoprotective transcription factor NFAT5, macrophages (MF) exert homeostatic regulatory function in the Na + -overladen interstitium of the skin and regulate Na + clearance from skin Na + stores through cutaneous lymph vessels, which lowers systemic blood pressure (Lee et al., 2014; Machnik et al., 2009; Wiig et al., 2013). In contrast, T cells exposed to high-salt microenvironments skew into a pro-inflammatory Th17 phenotype and worsen autoimmune disease (Kleinewietfeld et al., 2013; Wu et al., 2013). High-salt diets (HSDs) also aggravated Helicobacter pylori-induced inflammation and carcinogenesis (Gaddy et al., 2013). "
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    • "Increased dietary salt intake might be an environmental risk factor for the development of autoimmune diseases , as it has been found that it can induce pathogenic Th17 cells and related proinflammatory cytokines in EAE ( Kleinewietfeld et al . , 2013 ; Wu et al . , 2013 ) . Th17 cells have been involved in the development of MS ."
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