Synaptotagmin-1 overexpression under inflammatory conditions affects secretion in salivary glands from Sjögren's syndrome patients

• Published in: Journal of autoimmunity 2019-02, Vol.97, p.88-99
• Main 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
• Format: Article
• Language: English
• Subjects: Adult; Biomarkers; Biopsy; Ca2+ signaling; Calcium - metabolism; Calcium Signaling; Disease Susceptibility; Female; Gene Expression; Glycosylation; Humans; Immunohistochemistry; Male; Middle Aged; PI(4,5)P2; Salivary Glands - metabolism; Salivary Glands - pathology; Salivary secretion; Signal Transduction; Sjogren's Syndrome - diagnosis; Sjogren's Syndrome - etiology; Sjogren's Syndrome - metabolism; Sjögren's syndrome; Synaptotagmin I - genetics; Synaptotagmin-1; TNF-α; Tumor Necrosis Factor-alpha - metabolism; Young Adult
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2018.10.019

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 Ca2+ are significant factors controlling exocytosis in different secretory cells, the Ca2+ role being the most studied. Salivary acinar cells from SS-patients show a defective agonist-regulated intracellular Ca2+ 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 Ca2+ 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, Ca2+ 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 Ca2+ 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. •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 Ca2+ signaling and amylase secreti