Induction of pathogenic Th17 cells by inducible salt sensing kinase SGK1

By Chuan Wu, Nir Yosef, T. Thalhamer, Chen Zhu, S. Xiao, Y. Kishi, Aviv Regev, V. Kuchroo. Nature, 2013

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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.

Subfields: Immunology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/baa1f6520a2653312de5a30722b79e152312b321

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Citations in the corpus

Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013, background): “salt (NaCl) (37, 38) and short-chain fatty acids (39) can influence TH17 and Treg homeostasis, respectively.”
Impact of genetic polymorphisms on human immune cell gene expression (2018, positive): “…such as, the immune checkpoint molecule PDCD1 (PD-1) (Keir et al., 2008), the co-stimulatory molecule TNFRSF9 (4–1BB) (Watts, 2005), the co-inhibitory molecule CD59 (Sivasankar et al., 2009) and SGK1 (Wu et al., 2013), a kinase that regulates differentiation of T H 17 and T H 2 cells (Fig.”
Salt-responsive gut commensal modulates TH17 axis and disease (2017, positive): “Consequently, a HSD boosts T H 17 generation and exacerbates actively-induced experimental autoimmune encephalomyelitis (EAE)11,12, as a prototypic T H 17-driven autoimmune disease13.”
Single-cell Genomics Unveils Critical Regulators of Th17 cell Pathogenicity (2015, background): “, Geminin, Figure 2D), a strong correlation with a salt-induced pathogenic Th17 cell signature (Wu et al., 2013) (Figure 2A), and association with both canonical Th17 TFs (Stat3 andHif1a) and Th1-associated factors, including Rel and Stat4 (Figure 2E), which are associated with EAE (Hilliard et al.”
Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine. (2015, positive): “See also Figure S5. to be critically involved in Th17 cell differentiation (Tanaka et al., 2014; Wu et al., 2013), were among the differentially expressed genes identified in LA-treated T cells under Th17-cell-polarizing conditions.”