Lgr4 Gene Deficiency Increases Susceptibility and Severity of Dextran Sodium Sulfate-induced Inflammatory Bowel Disease in Mice
Lgr4 Gene Deficiency Increases Susceptibility and Severity of Dextran Sodium Sulfate-induced Inflammatory Bowel Disease in Mice
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Lgr4 基因缺陷增加小鼠右旋糖酐硫酸钠诱导的炎症性肠病的易感性和严重程度
DOI：
10.1074/jbc.m112.436204
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发表时间：
2013-03-29
影响因子：
4.8
通讯作者：
Li, Dali
中科院分区：
文献类型：
--
作者：
Liu, Shijie;Qian, Yu;Li, Dali
Lgr 4/Gpr 48是新发现的R-spondins受体之一，并增强Wnt信号传导，从而调节肠道内稳态。我们使用了一种亚型小鼠品系来确定Lgr 4在肠道炎症和恢复中的作用。用葡聚糖硫酸钠（DSS）诱导肠道炎症，然后是恢复期。检测肠道炎症症状和分子机制。我们发现Lgr 4（-/-）小鼠对DSS诱导的炎症性肠病的易感性和死亡率明显高于WT小鼠。Lgr 4缺乏导致肠道中潘氏细胞或干细胞的数量大大减少。在肠再生过程中，Lgr 4（-/-）小鼠肠上皮细胞的增殖而不是凋亡明显受损。当Wnt/β-连环蛋白信号通过与APC（min/+）小鼠杂交或通过用GSK-3 β抑制剂处理而重新激活时，潘氏细胞的数量部分恢复，并且在Lgr 4缺陷动物中由DSS诱导的炎性肠病引起的死亡率显著降低。因此，Lgr 4通过调节Wnt/β-连环蛋白信号传导途径，在维持肠道内稳态和保护免受炎性肠病中起关键作用。
Lgr4/Gpr48 is one of the newly identified R-spondins receptors and potentiates Wnt signaling, which regulates intestinal homeostasis. We used a hypomorphic mouse strain to determine the role of Lgr4 in intestinal inflammation and recovery. Intestinal inflammation was induced with dextran sulfate sodium (DSS) followed by a recovery period. Intestinal inflammation symptoms and molecular mechanisms were examined. We found that Lgr4(-/-) mice exhibited dramatically higher susceptibility to and mortality from DSS-induced inflammatory bowel disease than WT mice. Lgr4 deficiency resulted in greatly reduced numbers of either Paneth cells or stem cells in the intestine. During the intestinal regeneration process, cell proliferation but not apoptosis of intestinal epithelial cells was significantly impaired in Lgr4(-/-) mice. When Wnt/beta-catenin signaling was reactivated by crossing with APC(min/+) mice or by treating with a GSK-3 beta inhibitor, the number of Paneth cells was partially restored and the mortality caused by DSS-induced inflammatory bowel disease was strikingly reduced in Lgr4-deficient animals. Thus, Lgr4 is critically involved in the maintenance of intestinal homeostasis and protection against inflammatory bowel disease through modulation of the Wnt/beta-catenin signaling pathway.