ClC-3 chloride channel/antiporter defect contributes to inflammatory bowel disease in humans and mice
ClC-3 chloride channel/antiporter defect contributes to inflammatory bowel disease in humans and mice
复制标题
ClC-3 氯通道/逆向转运蛋白缺陷导致人类和小鼠炎症性肠病
DOI：
10.1136/gutjnl-2013-305168
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发表时间：
2014-10-01
期刊：
影响因子：
24.5
通讯作者：
Zhou, Jia-Guo
中科院分区：
文献类型：
--
作者：
Huang, Lin-Yan;He, Qing;Zhou, Jia-Guo
研究背景ClC-3通道/反向转运蛋白在多种细胞活动中起关键作用。在回肠和结肠中检测到ClC-3。目的探讨ClC-3在胃肠道中的作用。设计在给予葡聚糖硫酸钠（DSS）或2，4，6-三硝基苯磺酸（TNBS）后，通过组织学、细胞、分子和生物化学方法检查来自ClC-3−/−和野生型小鼠的肠。免疫印迹法和免疫组化法检测ClC-3的表达。结果UC或克罗恩病患者和DSS治疗小鼠的肠组织中ClC-3表达降低。ClC-3基因缺失增加了小鼠对DSS或TNBS诱导的实验性结肠炎的易感性，并阻止了肠道恢复。ClC-3缺陷通过线粒体途径促进DSS诱导的肠上皮细胞凋亡。ClC-3与电压依赖性阴离子通道1相互作用，该通道是调节线粒体细胞色素c释放的关键因素，但DSS处理降低了这种相互作用。此外，缺乏ClC-3减少了潘氏细胞的数量，并损害了抗菌肽的表达。这些改变导致上皮屏障功能障碍和肠道细菌侵入粘膜。结论ClC-3基因缺陷可能通过促进肠上皮细胞凋亡和Paneth细胞丢失参与IBD的发病过程，提示调控ClC-3基因表达可能成为IBD治疗的新策略。
Background ClC-3 channel/antiporter plays a critical role in a variety of cellular activities. ClC-3 has been detected in the ileum and colon. Objective To determine the functions of ClC-3 in the gastrointestinal tract. Design After administration of dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS), intestines from ClC-3−/− and wild-type mice were examined by histological, cellular, molecular and biochemical approaches. ClC-3 expression was determined by western blot and immunostaining. Results ClC-3 expression was reduced in intestinal tissues from patients with UC or Crohn's disease and from mice treated with DSS. Genetic deletion of ClC-3 increased the susceptibility of mice to DSS- or TNBS-induced experimental colitis and prevented intestinal recovery. ClC-3 deficiency promoted DSS-induced apoptosis of intestinal epithelial cells through the mitochondria pathway. ClC-3 interacts with voltage-dependent anion channel 1, a key player in regulation of mitochondria cytochrome c release, but DSS treatment decreased this interaction. In addition, lack of ClC-3 reduced the numbers of Paneth cells and impaired the expression of antimicrobial peptides. These alterations led to dysfunction of the epithelial barrier and invasion of commensal bacteria into the mucosa. Conclusions A defect in ClC-3 may contribute to the pathogenesis of IBD by promoting intestinal epithelial cell apoptosis and Paneth cell loss, suggesting that modulation of ClC-3 expression might be a new strategy for the treatment of IBD.