P2X7 receptor antagonism prevents IL-1β release from salivary epithelial cells and reduces inflammation in a mouse model of autoimmune exocrinopathy
P2X7 receptor antagonism prevents IL-1β release from salivary epithelial cells and reduces inflammation in a mouse model of autoimmune exocrinopathy
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DOI：
10.1074/jbc.m117.790741
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发表时间：
2017-10-06
影响因子：
4.8
通讯作者：
Weisman, Gary A.
中科院分区：
文献类型：
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作者：
Khalafalla, Mahmoud G.;Woods, Lucas T.;Weisman, Gary A.
唾液腺炎症是干燥综合征（SS）的一个标志，这是一种常见的自身免疫性疾病，其特征是唾液腺淋巴细胞浸润和唾液分泌丧失，主要发生于女性。 P2X7 受体 (P2X7R) 是一种 ATP 门控非选择性阳离子通道，可诱导细胞和组织（包括唾液腺上皮）的炎症反应。在免疫细胞中，P2X7R 激活通过诱导多蛋白复合物 NLRP3 型炎症小体的寡聚化，诱导促炎细胞因子的产生，包括 IL-1β 和 IL-18。在此，我们的结果表明，在原代小鼠颌下腺 (SMG) 上皮细胞中，P2X7R 激活还会诱导 NLRP3 炎性体的组装以及 IL-1 beta 的成熟和释放，而从 P2X7R 缺陷小鼠中分离的 SMG 细胞中不存在这种反应 (P2X7R(-/-))。 SMG 上皮细胞中 P2X7R 介导的 IL-1 β 释放依赖于跨膜 Na+ 和/或 K+ 通量以及热休克蛋白 90 (HSP90) 的激活，热休克蛋白 90 是 NLRP3 炎性体激活和稳定所需的蛋白质。此外，使用活性氧 (ROS) 清除剂 N-乙酰半胱氨酸和 Mito-TEMPO，我们确定线粒体活性氧是 P2X7R 介导的 IL-1 β 释放所必需的。最后，在唾液腺外分泌病的 CD28(-/-)、IFN gamma(-/-)、NOD.H-2(h4) 小鼠模型中体内施用 P2X7R 拮抗剂 A438079 可改善唾液腺炎症并增强卡巴胆碱诱导的唾液分泌。这些发现表明，体内 P2X7R 拮抗作用代表了一种有前途的限制唾液腺炎症和改善分泌功能的治疗策略。
Salivary 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.