Synaptotagmin-1 overexpression under inflammatory conditions affects secretion in salivary glands from Sjögren's syndrome patients. (February 2019)

• Record Type: Journal Article
• Authors: Cortés, Juan; Hidalgo, Jorge; Aguilera, Sergio; Castro, Isabel; Brito, Mónica; Urra, Hery; Pérez, Paola; Barrera, María-José; Carvajal, Patricia; Urzúa, Ulises; González, Sergio; Molina, Claudio; Bahamondes, Verónica; Hermoso, Marcela; González, María-Julieta
• Is Part Of: Journal of autoimmunity. Volume 97(2019)
• Page Start: 88
• Page End: 99
• Publication Date: 2019-02
• Subjects: Synaptotagmin-1 -- PI(4, 5)P2 -- Ca2+ signaling -- TNF-α -- Salivary secretion -- Sjögren's syndrome; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2018.10.019
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: Sjögren's syndrome (SS) is an autoimmune exocrinopathy associated with severe secretory alterations by disruption of the glandular architecture integrity, which is fundamental for a correct function and localization of the secretory machinery. Syt-1, PI(4, 5)P2 and Ca 2+ are significant factors controlling exocytosis in different secretory cells, the Ca 2+ role being the most studied. Salivary acinar cells from SS-patients show a defective agonist-regulated intracellular Ca 2+ release together with a decreased IP3R expression level, and this condition may explain a reduced water release. However, there are not reports where Syt-1, PI(4, 5)P2 and Ca 2+ in acinar cells of SS patients had been studied. In the present study, we analyzed the expression and/or localization of Syt-1 and PI(4, 5)P2 in acinar cells of labial salivary gland biopsies from SS-patients and control individuals. Also, we evaluated whether the overexpression of Syt-1 and the loss of cell polarity induced by TNF-α or loss of interaction between acinar cell and basal lamina, alters directionality of the exocytosis process, Ca 2+ signaling and α-amylase secretion in a 3D-acini model stimulated with cholinergic or β-adrenergic agonists. In addition, the correlation between Syt-1 protein levels and clinical parameters was evaluated. The results showed an increase of Syt-1 mRNA and protein levels, and a high number of co-localization points of Syt-1/STX4 and PI(4, 5)P2 /Ezrin in the acinar basolateral region of LSG from SS-patients. With regard to 3D-acini, Syt-1 overexpression increased exocytosis in the apical pole compared to control acini. TNF-α stimulation increased exocytic events in the basal pole, which was further enhanced by Syt-1 overexpression. Additionally, altered acinar cell polarity affected Ca 2+ signaling and amylase secretion. Overexpression of Syt-1 was associated with salivary gland alterations revealing that the secretory dysfunction in SS-patients is linked to altered expression and/or localization of secretory machinery components together with impaired epithelial cell polarity. These findings provide a novel insight on the pathological mechanism implicated in ectopic secretory products to the extracellular matrix of LSG from SS-patients, which might initiate inflammation. Highlights: Syt-1 is overexpressed and mislocated in SG from SS-patients (64). Syt-1 overexpression and TNF-α stimulation changes the secretion polarity (82). Altered cell polarity affects Ca 2+ signaling and amylase secretion (71). Syt-1 overexpression correlates with secretory dysfunction parameters in SS-patients (85). Strong association between Syt-1 overexpression with ESSDAI in SS-patients (74).