Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1

Abstract

Th17 cells are highly proinflammatory cells critical for clearing extracellular pathogens and for induction of multiple autoimmune diseases1. IL-23 plays 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 functions2, 3. 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 signaling network and nominate major nodes that regulate Th17 development. We identified serum glucocorticoid kinase-1 (SGK1), a serine-threonine kinase4, as an essential node downstream of IL-23 signaling. SGK1 is critical for regulating IL-23R expression and stabilizing the Th17 cell phenotype by deactivation of Foxo1, a direct repressor of IL-23R expression. SGK1 has been shown to govern Na+ transport and salt (NaCl) homeostasis in other cells5, 6, 7, 8. We here show 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 plays a critical role in the induction of pathogenic Th17 cells and provides a molecular insight into a mechanism by which an environmental factor such as a high salt diet triggers Th17 development and promotes tissue inflammation.

Western lifestyle and immunopathology of multiple sclerosis

“…In agreement with these findings, T H 17 cells generated under salt‐enriched conditions show a highly pathogenic phenotype in vitro 74, 75. This increase in T H 17 responses under high salt conditions was shown to be mediated by p38 mitogen‐activated protein kinase (MAPK), nuclear factor of activated T cells (NFAT5), and serum glucocorticoid kinase‐1 (SGK1) 74, 75. Consistently, a T cell–specific knockout of Sgk1 in mice ameliorated EAE disease severity that was seen on a high salt diet 75.…”

“…A possible explanation of these divergent results is the different treatments and baseline characteristics of the MS patients included in the studies, as well as the divergent approaches to assess sodium intake in these retrospective analyses. Several studies have shown that high sodium diets could exacerbate EAE 74, 75, 77, 79. When analyzing CD4 + T cells, this effect was accompanied by increased numbers of T H 17 cells and a higher infiltration of T H 17 cells into the CNS 74, 75.…”

“…The salt consumption varies considerably among countries, ranging from 1.5 g of sodium per day in East African countries to 3.9 g of sodium per day in high‐income countries 73. Recently, many studies have demonstrated that a high intake of sodium chloride can be an important factor potentially influencing autoimmunity in both humans and rodents 74, 75, 76, 77, 78, 79, 80, 81, 82. In patients with RRMS in Argentina, increased sodium intake was associated with enhanced disease exacerbation and new lesion development 76.…”

Effects of Intensive Low-Salt Diet Education on Albuminuria among Nondiabetic Patients with Hypertension Treated with Olmesartan

“…High salt intake also induces the intrarenal aldosterone receptor and promotes renal fibrotic injury (15). Two recent studies identified that increased dietary salt intake promotes tissue inflammation by triggering IL-17-producing CD4 + T cell development (16,17).…”

Effects of Sugar, Salt and Distilled Water on White Blood Cells and Platelet Cells

“…This condition is known as autoimmunity. Hence high intake of sodium produces high immune cells like helper T cells which attack healthy tissues by producing protein interleukin [27][28] .…”