Inflammation and disruption of the mucosal architecture in claudin-7-deficient mice.
Inflammation and disruption of the mucosal architecture in claudin-7-deficient mice.
复制标题
DOI：
10.1053/j.gastro.2011.10.025
复制
发表时间：
2012-02
期刊：
影响因子：
29.4
通讯作者：
Chen YH
中科院分区：
文献类型：
--
作者：
Ding L;Lu Z;Foreman O;Tatum R;Lu Q;Renegar R;Cao J;Chen YH
肠道上皮的完整性是营养、吸收和防御病原体所必需的。Claudins是一种细胞黏附分子，定位于紧密连接(TJ)；许多在肠道表达，但对其功能知之甚少。Claudin-7的独特之处在于它比其他Claudin有更强的基侧膜分布，后者主要定位于肠上皮中的顶端TJ。我们研究了Claudin-7的基侧功能，并评估了破坏Cldn7对小鼠肠道的影响。我们培育了Cldn7−/−小鼠，并通过组织学、分子和细胞生物学以及生化方法对它们的肠道进行了检查。我们使用小干扰(Si)RNA在上皮细胞系中进行了基因沉默实验。Cldn7−/−小鼠有严重的肠道缺陷，包括粘膜溃疡、上皮细胞脱落和炎症。Cldn7−/−小鼠的肠道产生显著更高水平的细胞因子、NF-κB p65亚单位和COX-2；它们还上调了基质金属蛋白酶(MMPs)-3和-7的表达。上皮细胞系中的siRNA显示，MMP3的表达增加是由于claudin-7的缺失，而MMP7的表达增加是由炎症引起的。电子显微镜分析显示，Cldn7-−/−小鼠的肠道在TJ以下有细胞间隙，细胞-基质疏松。Cldn7基因的缺失降低了整合素α2亚单位的表达，改变了整合素α2亚单位的定位；破坏了通常在肠上皮基外侧室形成的Claudin-7、整合素Cludin 2和Claudin-1复合体的形成。在小鼠中，claudin-7具有非TJ功能，包括维持上皮细胞-基质相互作用和肠道内环境稳定。
Integrity of the intestinal epithelium is required for nutrition absorption and defense against pathogens. Claudins are cell adhesion molecules that localize at tight junctions (TJs); many are expressed in the intestinal tract, but little is known about their functions. Claudin-7 is unique in that it has a stronger basolateral membrane distribution than other claudins, which localize primarily to apical TJs in the intestinal epithelium. We investigated the basolateral functions of claudin-7 and assessed the effects of disruption of Cldn7 in intestines of mice. We generated Cldn7−/− mice and examined their intestines by histology, molecular and cellular biology, and biochemistry approaches. We carried out gene silencing experiments in epithelial cell lines using small interfering (si)RNAs. The Cldn7−/− mice had severe intestinal defects that included mucosal ulcerations, epithelial cell sloughing, and inflammation. Intestines of Cldn7−/− mice produced significantly higher levels of cytokines, the NF-κB p65 subunit, and COX-2; they also upregulated expression of matrix metalloproteinases (MMPs)-3 and -7. siRNA in epithelial cell lines demonstrated that the increased expression of MMP-3 resulted directly from claudin-7 depletion, whereas that of MMP-7 resulted from inflammation. Electron microscopy analysis showed that intestines of Cldn7−/− mice had intercellular gaps below TJs and cell-matrix loosening. Deletion of Cldn7 reduced expression and altered localization of the integrin α2 subunit; disrupted formation of complexes of claudin-7, integrin α2, and claudin-1 that normally form in epithelial basolateral compartments of intestines. In mice, claudin-7 has non-TJ functions, including maintenance of epithelial cell–matrix interactions and intestinal homeostasis.
登录
查看更多内容
影响因子：
29.4
作者：
Fox, JG;Li, XT;Wang, TC
通讯作者：
Wang, TC
影响因子：
7.8
作者：
Furuse, Mikio;Hata, Masaki;Furuse, Kyoko;Yoshida, Yoko;Haratake, Akinori;Sugitani, Yoshinobu;Noda, Tetsuo;Kubo, Akiharu;Tsukita, Shoichiro
通讯作者：
Tsukita, Shoichiro
影响因子：
7.8
作者：
Nitta, T;Hata, M;Tsukita, S
通讯作者：
Tsukita, S
影响因子：
15.9
作者：
Smalley-Freed, Whitney G.;Efimov, Andrey;Reynolds, Albert B.
通讯作者：
Reynolds, Albert B.
影响因子：
29.4
作者：
Tamura, Atsushi;Kitano, Yuka;Tsukita, Sachiko
通讯作者：
Tsukita, Sachiko