VIP/VPAC1 relative expression in salivary glands as an endogenous modulator of acinar cell apoptosis in a murine model of Sjögren?s syndrome.

V. HAUK; CALAFAT M; L. LAROCCA; L. FRACCAROLI; E. GRASSO; R. RAMHORST; C. PÉREZ LEIRÓS

Clinical & Experimental Immunology

Wiley-Blackwell

Año: 2011 vol. 166 p. 309 - 316

1365-2249

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 of salivary dysfunction with acinar cells actively involved in the pathogenesis of SS. The nonobese 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/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 as compared with normal mice. The deep loss of endogenous VIP was associated to a loss of acinar cells through apoptotic mechanisms that could be further induced by TNF-α and reversed by VIP through a cAMP/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.