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J Biol Chem. 2017 Oct 6;292(40):16626-16637. doi: 10.1074/jbc.M117.790741. Epub 2017 Aug 10.

P2X7 receptor antagonism prevents IL-1β release from salivary epithelial cells and reduces inflammation in a mouse model of autoimmune exocrinopathy.

Author information

1
From the Department of Biochemistry.
2
Christopher S. Bond Life Sciences Center, and.
3
the Department of Nutritional Sciences, University of Arizona, Tucson, Arizona, 85721.
4
Department of Nutrition and Exercise Physiology,University of Missouri, Columbia, Missouri, 65211-7310 and.
5
From the Department of Biochemistry, weismang@missouri.edu.

Abstract

Salivary gland inflammation is a hallmark of Sjögren'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-1β 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-1β, a response that is absent in SMG cells isolated from mice deficient in P2X7Rs (P2X7R-/-). P2X7R-mediated IL-1β 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-1β release. Lastly, in vivo administration of the P2X7R antagonist A438079 in the CD28-/-, IFNγ-/-, NOD.H-2h4 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.

KEYWORDS:

ATP; IL-1β; P2X7; P2X7 receptor; Sjögren's syndrome; autoimmune disease; inflammasome; inflammation; purinergic receptor; salivary gland

PMID:
28798231
PMCID:
PMC5633125
DOI:
10.1074/jbc.M117.790741
[Indexed for MEDLINE]
Free PMC Article

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