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Role of high salt diet and transcription factor NFTA5 on Sjögren's syndrome


Sjögren's syndrome (SS) is a chronic autoimmune disorder characterized by dysfunction of the exocrine glands, including salivary and lacrymal glands. SS immunopathology results from the interplay between immune and epithelial cells; the latter play an important pathogenic role in SS as suggested by the presence of infiltrating lesions (epithelitis) as well as the increased epithelial expression of immunoactive proteins (IMAP) involved in the recruitment, activation, differentiation and propagation of inflammatory cells. IMAP include antigen presentation, costimulatory and adhesion molecules, as well as various proinflammatory cytokines, B-cell differentiating factors and T-cell attracting and germinal-center-forming chemokines. High salt diet (HSD) has been shown to drive and exacerbate autoimmune disease by induction of IL-17-producing CD4+ helper T cells (TH17), while TH17-IL17 axis has been implicated in the pathogenesis of SS. High-salt conditions, subjecting cells to hyperosmolar stress (HOS), triggers the activation of protein kinases leading to the phosphorylation and activation of Nuclear Factor of Activated T-cells 5 (NFAT5) (a transcription factor also termed tonicity-responsive enhancer binding protein - TonEBP), resulting in the transactivation of osmoprotective genes ensuring intracellular osmolytes accumulation. In addition to its osmoprotective role, NFAT5 has been implicated in the HOS-induced production of pro-inflammatory cytokines, including IL-17, by mononuclear and epithelial cells. During the first phase of saliva formation, the secretion of NaCl by acinar cells induces a transepithelial osmotic gradient, resulting in water transport from acinar cells to their apical lumen. Transcellular water transport is ensured by aquaporin-5 (AQP5), a member of the family of water channels, expressed in salivary gland (SG) acinar cells and playing a major role in saliva secretion. In SS, acinar cells destruction and altered acinar AQP5 localization (mostly basolateral instead of apical) contribute to the formation of a chronic osmotic gradient resulting from both reduced water flow and KHCO3 secretion by ductal cells. Consequently, SG epithelial cells are most likely exposed chronically to HOS during the course of SS. The main goal of the project is to determine the effect of high salt diet on Sjögren's syndrome. To reach this goal, we will employ the following strategies: 1) characterize in-depth the DMXAA-induced SS mouse model; 2) investigate the impact of NFAT5 and HSD on the DMXAA-induced SS mouse model. Additionally, we will organize research seminars and scientific workshops for knowledge diffusion and to improve collaborative bilateral scientific actions. (AU)

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