P2X7 receptor antagonism prevents IL-1β release from salivary epithelial cells and reduces inflammation in a mouse model of autoimmune exocrinopathy
AuthorKhalafalla, Mahmoud G.
Woods, Lucas T.
Camden, Jean M.
Khan, Aslam A.
Limesand, Kirsten H.
Petris, Michael J.
Weisman, Gary A.
AffiliationUniv Arizona, Dept Nutr Sci
MetadataShow full item record
CitationP2X7 receptor antagonism prevents IL-1β release from salivary epithelial cells and reduces inflammation in a mouse model of autoimmune exocrinopathy 2017, 292 (40):16626 Journal of Biological Chemistry
JournalJournal of Biological Chemistry
Rights© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractSalivary gland inflammation is a hallmark of Sjogren's syndrome (SS), a common autoimmune disease characterized by lymphocytic infiltration of the salivary gland and loss of saliva secretion, predominantly in women. The P2X7 receptor (P2X7R) is an ATP-gated nonselective cation channel that induces inflammatory responses in cells and tissues, including salivary gland epithelium. In immune cells, P2X7R activation induces the production of proinflammatory cytokines, including IL-1 beta and IL-18, by inducing the oligomerization of the multiprotein complex NLRP3-type inflammasome. Here, our results show that in primary mouse submandibular gland (SMG) epithelial cells, P2X7R activation also induces the assembly of the NLRP3 inflammasome and the maturation and release of IL-1 beta, a response that is absent in SMG cells isolated from mice deficient in P2X7Rs (P2X7R(-/-)). P2X7R-mediated IL-1 beta release in SMG epithelial cells is dependent on transmembrane Na+ and/or K+ flux and the activation of heat shock protein 90 (HSP90), a protein required for the activation and stabilization of the NLRP3 inflammasome. Also, using the reactive oxygen species (ROS) scavengers N-acetyl cysteine and Mito-TEMPO, we determined that mitochondrial reactive oxygen species are required for P2X7R-mediated IL-1 beta release. Lastly, in vivo administration of the P2X7R antagonist A438079 in the CD28(-/-), IFN gamma(-/-), NOD.H-2(h4) mouse model of salivary gland exocrinopathy ameliorated salivary gland inflammation and enhanced carbachol-induced saliva secretion. These findings demonstrate that P2X7R antagonism in vivo represents a promising therapeutic strategy to limit salivary gland inflammation and improve secretory function.
Note12 month embargo; Published online: 10 Aug 17.
VersionFinal published version
SponsorsNational Institute of Dental and Craniofacial Research, National Institutes of Health [DE023342]