p120-catenin is essential for maintenance of barrier function and intestinal homeostasis in mice
p120-catenin is essential for maintenance of barrier function and intestinal homeostasis in mice
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DOI：
10.1172/jci41414
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发表时间：
2010-06-01
影响因子：
15.9
通讯作者：
Reynolds, Albert B.
中科院分区：
文献类型：
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作者：
Smalley-Freed, Whitney G.;Efimov, Andrey;Reynolds, Albert B.
上皮钙粘蛋白（E-钙粘蛋白）是上皮表型的主要组织者。其功能部分受 p120-连环蛋白（本文称为 p120）调节，p120-连环蛋白是直接调节钙粘蛋白稳定性的细胞质结合配偶体。由于钙粘蛋白在炎症性肠病 (IBD) 中发挥作用，我们试图通过评估 p120 缺乏对小鼠小肠和结肠的影响来进一步研究这一点。 p120条件性敲除小鼠出生时表面正常，但病情迅速恶化，并在21天内死亡。细胞间粘附缺陷和炎症导致进行性粘膜糜烂和终末出血，类似于在 IBD 显性失活钙粘蛋白小鼠模型中观察到的情况。此外，还观察到粘附连接的选择性丧失和非典型 COX-2 表达的中性粒细胞在结肠 p120 缺失区域的积累。为了阐明这一机制，我们在体外评估了极化结肠癌细胞系中 p120 缺陷的直接影响。值得注意的是，跨上皮电阻显着降低，中性粒细胞结合增加 30 倍，并且中性粒细胞中 COX-2（一种与 IBD 相关的酶）水平显着增加。我们的数据表明，p120 的缺失会破坏新生儿肠道屏障并放大中性粒细胞的参与，并且这些变化会导致细菌和其他管腔抗原在新生儿肠道定植期间发生灾难性炎症。因此，我们得出结论，p120 在肠道屏障功能、上皮稳态和存活中具有重要作用。
Epithelial-cadherin (E-cadherin) is a master organizer of the epithelial phenotype. Its function is regulated in part by p120-catenin (referred to herein as p120), a cytoplasmic binding partner that directly regulates cadherin stability. As it has been suggested that cadherins have a role in inflammatory bowel disease (IBD), we sought to investigate this further by assessing the effect of p120 deficiency in mouse small intestine and colon. p120 conditional KO mice were superficially normal at birth but declined rapidly and died within 21 days. Cell-cell adhesion defects and inflammation led to progressive mucosal erosion and terminal bleeding, similar to what is observed in a dominant-negative cadherin mouse model of IBD. Additionally, selective loss of adherens junctions and accumulation of atypical COX-2-expressing neutrophils in p120-null areas of the colon were observed. To elucidate the mechanism, direct effects of p120 deficiency were assessed in vitro in a polarizing colon cancer cell line. Notably, transepithelial electrical resistance was dramatically reduced, neutrophil binding was increased 30 fold, and levels of COX-2, an enzyme associated with IBD, were markedly increased in neutrophils. Our data suggest that p120 loss disrupts the neonatal intestinal barrier and amplifies neutrophil engagement and that these changes lead to catastrophic inflammation during colonization of the neonatal gut with bacteria and other luminal antigens. Thus, we conclude that p120 has an essential role in barrier function and epithelial homeostasis and survival in the intestine.