E-cadherin Is Critical for Collective Sheet Migration and Is Regulated by the Chemokine CXCL12 Protein During Restitution
E-cadherin Is Critical for Collective Sheet Migration and Is Regulated by the Chemokine CXCL12 Protein During Restitution
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DOI：
10.1074/jbc.m112.367979
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发表时间：
2012-06-22
影响因子：
4.8
通讯作者：
Dwinell, Michael B.
中科院分区：
文献类型：
--
作者：
Hwang, Soonyean;Zimmerman, Noah P.;Dwinell, Michael B.
趋化因子和其他免疫介质增强上皮屏障修复。肠屏障是通过上皮细胞之间高度调节的细胞-细胞接触建立的。这些研究的目的是确定趋化因子CXCL 12在上皮恢复过程中集体片层迁移过程中调节E-钙粘蛋白的作用。使用Caco 2（BBE）和IEC-6模型上皮研究调节E-cadherin的机制。基因敲除证实了E-钙粘蛋白在体外恢复和体内伤口修复中的关键作用。在恢复过程中，CXCL 12和TGF-β 1通过减少迁移上皮细胞之间的细胞旁间隙来收紧单层。然而，CXCL 12与TGF-β 1的不同之处在于刺激恢复过程中E-钙粘蛋白膜定位的显著增加。趋化因子刺激的E-钙粘蛋白的重新定位是通过增加极化上皮的屏障完整性在恢复过程中。CXCL 12激活其同源受体CXCR 4刺激E-钙粘蛋白定位和单层收紧通过Rho相关的蛋白激酶激活和F-肌动蛋白重组。这些数据证明了E-钙粘蛋白在肠上皮恢复中的关键作用。
Chemokines and other immune mediators enhance epithelial barrier repair. The intestinal barrier is established by highly regulated cell-cell contacts between epithelial cells. The goal of these studies was to define the role for the chemokine CXCL12 in regulating E-cadherin during collective sheet migration during epithelial restitution. Mechanisms regulating E-cadherin were investigated using Caco2(BBE) and IEC-6 model epithelia. Genetic knockdown confirmed a critical role for E-cadherin in in vitro restitution and in vivo wound repair. During restitution, both CXCL12 and TGF-beta 1 tightened the monolayer by decreasing the paracellular space between migrating epithelial cells. However, CXCL12 differed from TGF-beta 1 by stimulating the significant increase in E-cadherin membrane localization during restitution. Chemokine-stimulated relocalization of E-cadherin was paralleled by an increase in barrier integrity of polarized epithelium during restitution. CXCL12 activation of its cognate receptor CXCR4 stimulated E-cadherin localization and monolayer tightening through Rho-associated protein kinase activation and F-actin reorganization. These data demonstrate a key role for E-cadherin in intestinal epithelial restitution.