P2Y2 receptor antagonism resolves sialadenitis and improves salivary flow in a Sjögren's syndrome mouse model. (April 2021)

• Record Type: Journal Article
• Authors: Jasmer, Kimberly J.; Woods, Lucas T.; Forti, Kevin Muñoz; Martin, Adam L.; Camden, Jean M.; Colonna, Marco; Weisman, Gary A.
• Is Part Of: Archives of oral biology. Volume 124(2021)
• Publication Date: 2021-04
• Subjects: P2Y2R P2Y2 receptor -- IFNγ interferon gamma -- P2X7R P2X7 receptor -- SMG submandibular gland -- SS Sjögren's syndrome -- UTP uridine 5′-triphosphate; Sjögren's syndrome -- Purinergic receptor -- Nucleotide -- B lymphocytes -- Autoimmune disease -- Alarmins; Mouth -- Periodicals; Mouth -- Diseases -- Periodicals; Dentistry -- Periodicals; Electronic journals; 617.6005
• DOI: 10.1016/j.archoralbio.2021.105067
• Languages: English
• ISSNs: 0003-9969

Abstract

Highlights: Systemic or localized delivery of the selective P2Y2R antagonist, AR-C118925, were evaluated in the NOD.H-2 h4, IFNγ −/−, CD28 −/− SS mouse model. Systemic administration of AR-C118925 resolves salivary gland inflammation and improves saliva flow in NOD.H-2 h4, IFNγ −/−, CD28 −/− mice. Single-dose localized administration of AR-C118925 did not resolve inflammation or affect saliva flow in NOD.H-2 h4, IFNγ −/−, CD28 −/− mice. Functional P2Y2 Rs are expressed in isolated salivary gland B lymphocytes. P2Y2 Rs expressed in salivary gland B lymphocytes promote migration and IgM secretion. Abstract: Objective: Sjögren's syndrome (SS) is a chronic autoimmune exocrinopathy characterized by lymphocytic infiltration of the salivary and lacrimal glands and decreased saliva and tear production. Previous studies indicate that the G protein-coupled P2Y2 nucleotide receptor (P2Y2 R) is upregulated in numerous models of salivary gland inflammation ( i.e., sialadenitis), where it has been implicated as a key mediator of chronic inflammation. Here, we evaluate both systemic and localized P2Y2 R antagonism as a means to resolve sialadenitis in the NOD.H-2 h4, IFNγ −/−, CD28 −/− (NOD.H-2 h4 DKO) mouse model of SS. Design: Female 4.5 month old NOD.H-2 h4 DKO mice received daily intraperitoneal injections for 10 days of the selective P2Y2 R antagonist, AR-C118925, or vehicle-only control. Single-dose localized intraglandular antagonist delivery into the Wharton's duct was also evaluated. Carbachol-induced saliva was measured and then submandibular glands (SMGs) were isolated and either fixed and paraffin-embedded for H&E staining, homogenized for RNA isolation or dissociated for flow cytometry analysis. Results: Intraperitoneal injection, but not localized intraglandular administration, of AR-C118925 significantly enhanced carbachol-induced salivation and reduced lymphocytic foci and immune cell markers in SMGs of 5 month old NOD.H-2 h4 DKO mice, compared to vehicle-injected control mice. We found that B cells represent the primary immune cell population in inflamed SMGs of NOD.H-2 h4 DKO mice that express elevated levels of P2Y2 R compared to C57BL/6 control mice. We further demonstrate a role for P2Y2 Rs in mediating B cell migration and the release of IgM. Conclusion: Our findings suggest that the P2Y2 R represents a novel therapeutic target for the treatment of Sjögren's syndrome.