Matrix metalloproteinase 7 contributes to intestinal barrier dysfunction by degrading tight junction protein Claudin-7.
Matrix metalloproteinase 7 contributes to intestinal barrier dysfunction by degrading tight junction protein Claudin-7.
复制标题
DOI：
10.3389/fimmu.2022.1020902
复制
发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
先前的研究表明基质金属蛋白酶（MMPs），如MMP-7，在炎症性肠病（IBD）中表现出在肠道炎症期间增加的活性。然而，MMP-7的病理生理作用尚未清楚阐明。在溃疡性结肠炎（UC）患者的结肠活检、实验性结肠炎啮齿动物以及细胞因子检测中评估了MMP-7的表达。用葡聚糖硫酸钠（DSS）或三硝基苯磺酸处理野生型和MMP-7缺失小鼠，测定体内MMP-7的促炎功能。MMP-7在UC患者和实验性结肠炎啮齿动物中高表达。IL-1β、IL-4、IL-13、TNFα或脂多糖可增强人结肠上皮细胞、大鼠结肠平滑肌细胞和thp -1来源的巨噬细胞中MMP-7的表达。活性MMP-7在上皮细胞中降解紧密连接蛋白Claudin-7，在无细胞系统中裂解重组Claudin-7，增加Caco-2单层通透性。结肠活检免疫染色显示UC患者MMP-7上调，Claudin-7降低。与野生型小鼠相比，Mmp7 -/-小鼠在DSS损伤后结肠炎症明显减轻。dss诱导的连接蛋白改变在Mmp7 -/-小鼠中得到缓解，这表明MMP-7破坏了肠道屏障。MMP-7抗体显著改善了2种不同结肠炎模型的结肠炎症和Claudin-7的减少。MMP-7通过裂解cludin -7破坏肠上皮屏障，从而加重炎症。这些研究发现Claudin-7是肠上皮中MMP-7的新底物，并增强了MMP-7作为IBD的潜在治疗靶点。
Previous studies implicated matrix metalloproteinases (MMPs), such as MMP-7, in inflammatory bowel diseases (IBD) by showing increased activity during inflammation of the gut. However, the pathophysiological roles of MMP-7 have not been clearly elucidated. The expression of MMP-7 was assessed in colonic biopsies of patients with ulcerative colitis (UC), in rodents with experimental colitis, and in cell-based assays with cytokines. Wild-type and MMP-7-null mice treated with dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid were used for determining the pro-inflammatory function(s) of MMP-7 in vivo. MMP-7 was highly expressed in patients with UC and in rodents with experimental colitis. IL-1β, IL-4, IL-13, TNFα, or lipopolysaccharide enhanced MMP-7 expression in human colonic epithelial cells, rat colonic smooth muscle cells, and THP-1-derived macrophages. Active MMP-7 degraded tight junction protein Claudin-7 in epithelial cells, cleaved recombinant Claudin-7 in cell-free system, and increased Caco-2 monolayer permeability. Immunostaining of colon biopsies revealed up-regulation of MMP-7 and reduction of Claudin-7 in UC patients. Compared to wild-type mice, Mmp7 -/- mice had significantly less inflammation in the colon upon DSS insult. DSS-induced alterations in junction proteins were mitigated in Mmp7 -/- mice, suggesting that MMP-7 disrupts the intestinal barrier. MMP-7 antibody significantly ameliorated colonic inflammation and Claudin-7 reduction in 2 different rodent models of colitis. MMP-7 impairs intestinal epithelial barrier by cleavage of Claudin-7, and thus aggravating inflammation. These studies uncovered Claudin-7 as a novel substrate of MMP-7 in the intestinal epithelium and reinforced MMP-7 as a potential therapeutic target for IBD.
登录
查看更多内容
影响因子：
5.4
作者：
Manon-Jensen, Tina;Multhaupt, Hinke A. B.;Couchman, John R.
通讯作者：
Couchman, John R.
DOI：
10.1038/nri.2016.88
发表时间：
2016-10
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Johansson ME;Hansson GC
通讯作者：
Hansson GC
影响因子：
4.3
作者：
Landy, Jonathan;Ronde, Emma;Al-Hassi, Hafid Omar
通讯作者：
Al-Hassi, Hafid Omar
影响因子：
4.8
作者：
Li, QJ;Dashwood, RH
通讯作者：
Dashwood, RH
DOI：
10.1124/jpet.106.103465
发表时间：
2006-09-01
影响因子：
3.5
作者：
Medina, Carlos;Radomski, Marek W.
通讯作者：
Radomski, Marek W.