P2Y2 receptor antagonism resolves sialadenitis and improves salivary flow in a Sjögren’s syndrome mouse model
In: Archives of Oral Biology, Jg. 124 (2021-04-01), S. 105067-105067
Online
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Zugriff:
Objective Sjogren’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 (P2Y2R) 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 P2Y2R antagonism as a means to resolve sialadenitis in the NOD.H-2h4,IFNγ−/−,CD28−/− (NOD.H-2h4 DKO) mouse model of SS. Design Female 4.5 month old NOD.H-2h4 DKO mice received daily intraperitoneal injections for 10 days of the selective P2Y2R 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-2h4 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-2h4 DKO mice that express elevated levels of P2Y2R compared to C57BL/6 control mice. We further demonstrate a role for P2Y2Rs in mediating B cell migration and the release of IgM. Conclusion Our findings suggest that the P2Y2R represents a novel therapeutic target for the treatment of Sjogren’s syndrome.
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P2Y2 receptor antagonism resolves sialadenitis and improves salivary flow in a Sjögren’s syndrome mouse model
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Autor/in / Beteiligte Person: | Martin, Adam L. ; Jasmer, Kimberly J. ; Kevin Muñoz Forti ; Weisman, Gary A. ; Camden, Jean M. ; Colonna, Marco ; Woods, Lucas T. |
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Zeitschrift: | Archives of Oral Biology, Jg. 124 (2021-04-01), S. 105067-105067 |
Veröffentlichung: | Elsevier BV, 2021 |
Medientyp: | unknown |
ISSN: | 0003-9969 (print) |
DOI: | 10.1016/j.archoralbio.2021.105067 |
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