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: 41.46). 03/2013; 496(7446). DOI: 10.1038/nature11984
Source: PubMed


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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Available from: Sheng qiang Xiao, Oct 31, 2014
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    • "To confirm that Th17 plasticity contributed to the pathogenic profile of T cells primed with DC-Il2 À/À cells, we investigated whether Th17 cells differentiated under conditions of IL-2 deficiency exhibited the pathogenic signature that has been associated with immune pathology across several settings (Lee et al., 2012). Within these settings, IL-23 contributes to the emergence of pathogenic Th17 effector cells (Wu et al., 2013). We measured mRNA levels of a panel of 13 markers (Table S2) in T cells, including surface receptors, nuclear receptors, transcription factors , and cytokines that have been associated with the pathogenic Th17 signature described above (Korn et al., 2009; Muranski et al., 2011; Wu et al., 2013; Yosef et al., 2013). "
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    ABSTRACT: Th17 cells express diverse functional programs while retaining their Th17 identity, in some cases exhibiting a stem-cell-like phenotype. Whereas the importance of Th17 cell regulation in autoimmune and infectious diseases is firmly established, the signaling pathways controlling their plasticity are undefined. Using a mouse model of invasive pulmonary aspergillosis, we found that lung CD103(+) dendritic cells (DCs) would produce IL-2, dependent on NFAT signaling, leading to an optimally protective Th17 response. The absence of IL-2 in DCs caused unrestrained production of IL-23 and fatal hyperinflammation, which was characterized by strong Th17 polarization and the emergence of a Th17 stem-cell-like population. Although several cell types may be affected by deficient IL-2 production in DCs, our findings identify the balance between IL-2 and IL-23 productions by lung DCs as an important regulator of the local inflammatory response to infection.
    Cell Reports 09/2015; DOI:10.1016/j.celrep.2015.08.030 · 8.36 Impact Factor
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    • "Notable amongst these have been gene expression profiling experiments to identify differentially expressed genes. This approach has been more successful for Th17 cell differentiation, pointing to the transcription factors Batf, Ahr and Ikzf3 and the sodium chloride sensor Sgk1 (Veldhoen et al., 2008; Schraml et al., 2009; Wu et al., 2013), than for T reg cell differentiation. Such findings have implications for diagnostic efforts and advancing our understanding of disease pathophysiology. "
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    ABSTRACT: The balance between Th17 and T regulatory (Treg) cells critically modulates immune homeostasis, with an inadequate Treg response contributing to inflammatory disease. Using an unbiased chemical biology approach, we identified a novel role for the dual specificity tyrosine-phosphorylation-regulated kinase DYRK1A in regulating this balance. Inhibition of DYRK1A enhances Treg differentiation and impairs Th17 differentiation without affecting known pathways of Treg/Th17 differentiation. Thus, DYRK1A represents a novel mechanistic node at the branch point between commitment to either Treg or Th17 lineages. Importantly, both Treg cells generated using the DYRK1A inhibitor harmine and direct administration of harmine itself potently attenuate inflammation in multiple experimental models of systemic autoimmunity and mucosal inflammation. Our results identify DYRK1A as a physiologically relevant regulator of Treg cell differentiation and suggest a broader role for other DYRK family members in immune homeostasis. These results are discussed in the context of human diseases associated with dysregulated DYRK activity.
    eLife Sciences 05/2015; 4. DOI:10.7554/eLife.05920 · 9.32 Impact Factor
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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.
    Journal of Autoimmunity 05/2015; 343. DOI:10.1016/j.jaut.2015.04.006 · 8.41 Impact Factor
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