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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    • "pathology and decreased clinical scores compared to WT mice given a high sodium diet. Wu et al. further showed that in vitro culture of undifferentiated Th lymphocytes in a high-sodium milieu enhanced Th17 polarization suggesting that the effect of sodium could act directly on Th lymphocytes (Wu et al., 2013). Thus the two research groups have come to the same conclusion that increased salt concentrations aggravate autoimmune disease by enhancing the stimulation of the production of interleukin-17-producing "
    09/2015; 21(3):131-134. DOI:10.15616/BSL.2015.21.3.131
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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; 12(11). DOI:10.1016/j.celrep.2015.08.030 · 8.36 Impact Factor
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    • "Thus, increasing attention is being paid to environmental factors and their impact in the immune response and T cell differentiation in particular. For example: several compounds present in household products can activate the aryl hydrocarbon receptor and impact both Th17 and regulatory cell differentiation (Quintana et al., 2008); sodium in westernized diet and processed foods can also enhance Th17 cell differentiation (Wu et al., 2013); the composition of commensal microbiota impacts T cell differentiation and response (Lathrop et al., 2011); and the lack of sun exposure and dietary habits can diminish vitamin D levels and affect regulatory cell function (Correale et al., 2009). Each of these environmental factors trigger different signaling pathways and the characterization of the complex interaction between them can shed light on the impact of the environment on the immune system. "
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    ABSTRACT: Seasonal changes in disease activity have been observed in multiple sclerosis, an autoimmune disorder that affects the CNS. These epidemiological observations suggest that environmental factors influence the disease course. Here, we report that melatonin levels, whose production is modulated by seasonal variations in night length, negatively correlate with multiple sclerosis activity in humans. Treatment with melatonin ameliorates disease in an experimental model of multiple sclerosis and directly interferes with the differentiation of human and mouse T cells. Melatonin induces the expression of the repressor transcription factor Nfil3, blocking the differentiation of pathogenic Th17 cells and boosts the generation of protective Tr1 cells via Erk1/2 and the transactivation of the IL-10 promoter by ROR-α. These results suggest that melatonin is another example of how environmental-driven cues can impact T cell differentiation and have implications for autoimmune disorders such as multiple sclerosis.
    Cell 09/2015; 162(6):1338-1352. DOI:10.1016/j.cell.2015.08.025 · 32.24 Impact Factor
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