TY - JOUR
T1 - P2X7 receptor antagonism prevents IL-1 release from salivary epithelial cells and reduces inflammation in a mouse model of autoimmune exocrinopathy
AU - Khalafalla, Mahmoud G.
AU - Woods, Lucas T.
AU - Camden, Jean M.
AU - Khan, Aslam A.
AU - Limesand, Kirsten H.
AU - Petris, Michael J.
AU - Erb, Laurie
AU - Weisman, Gary A.
N1 - Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.
PY - 2017/10/6
Y1 - 2017/10/6
N2 - 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-1 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, a response that is absent in SMG cells isolated from mice deficient in P2X7Rs (P2X7R/). P2X7R-mediated IL-1 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 release. Lastly, in vivo administration of the P2X7R antagonist A438079 in the CD28/, IFN/, 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.
AB - 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-1 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, a response that is absent in SMG cells isolated from mice deficient in P2X7Rs (P2X7R/). P2X7R-mediated IL-1 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 release. Lastly, in vivo administration of the P2X7R antagonist A438079 in the CD28/, IFN/, 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.
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U2 - 10.1074/jbc.M117.790741
DO - 10.1074/jbc.M117.790741
M3 - Article
C2 - 28798231
AN - SCOPUS:85030790451
SN - 0021-9258
VL - 292
SP - 16626
EP - 16637
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 40
ER -