title: Vasoactive intestinal peptide/vasoactive intestinal peptide receptor relative expression in salivary glands as one endogenous modulator of acinar cell apoptosis in a murine model of Sjögren's syndrome.
abstract: Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by a progressive oral and ocular dryness that correlates poorly with the autoimmune damage of the glands. It has been proposed that a loss of homeostatic equilibrium in the glands is partly responsible for salivary dysfunction with acinar cells involved actively in the pathogenesis of SS. The non-obese diabetic (NOD) mouse model of Sjögren's syndrome develops secretory dysfunction and early loss of glandular homeostatic mechanisms, with mild infiltration of the glands. Based on the vasodilator, prosecretory and trophic effects of the vasoactive intestinal peptide (VIP) on acini as well as its anti-inflammatory properties we hypothesized that the local expression of VIP/vasoactive intestinal peptide receptor (VPAC) system in salivary glands could have a role in acinar cell apoptosis and macrophage function thus influencing gland homeostasis. Here we show a progressive decline of VIP expression in submandibular glands of NOD mice with no changes in VPAC receptor expression compared with normal mice. The deep loss of endogenous VIP was associated with a loss of acinar cells through apoptotic mechanisms that could be induced further by tumour necrosis factor (TNF)-α and reversed by VIP through a cyclic adenosine-5'-monophosphate (cAMP)/protein kinase A (PKA)-mediated pathway. The clearance of apoptotic acinar cells by macrophages was impaired for NOD macrophages but a shift from inflammatory to regulatory phenotype was induced in macrophages during phagocytosis of apoptotic acinar cells. These results support that the decline in endogenous VIP/VPAC local levels might influence the survival/apoptosis intracellular set point in NOD acinar cells and their clearance, thus contributing to gland homeostasis loss.
authors: Laboratorio de Inmunofarmacología. Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina.
authors: V
authors: V
authors: Hauk
authors: M
authors: M
authors: Calafat
authors: L
authors: L
authors: Larocca
authors: L
authors: L
authors: Fraccaroli
authors: E
authors: E
authors: Grasso
authors: R
authors: R
authors: Ramhorst
authors: C Pérez
authors: CP
authors: Leirós
mesh_terms: D061354:Acinar Cells / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000473:pathology; D002470:Cell Survival; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016328:NF-kappa B / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D018005:Receptors, Vasoactive Intestinal Peptide / Q000096:biosynthesis*; D012859:Sjogren's Syndrome / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D013363:Submandibular Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D018005:Receptors, Vasoactive Intestinal Peptide; D014409:Tumor Necrosis Factor-alpha; D014660:Vasoactive Intestinal Peptide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases