Matrix metalloproteinase 7 contributes to intestinal barrier dysfunction by degrading tight junction protein Claudin-7.

Autor:	Xiao Y; Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, China.; Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, TX, United States., Lian H; Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China., Zhong XS; Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, TX, United States., Krishnachaitanya SS; Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, TX, United States., Cong Y; Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX, United States., Dashwood RH; Center for Epigenetics & Disease Prevention, Texas A&M College of Medicine, Houston, TX, United States., Savidge TC; Texas Children's Microbiome Center, Baylor College of Medicine, Houston, TX, United States., Powell DW; Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, TX, United States., Liu X; Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, China., Li Q; Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, TX, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2022 Oct 04; Vol. 13, pp. 1020902. Date of Electronic Publication: 2022 Oct 04 (Print Publication: 2022).
DOI:	10.3389/fimmu.2022.1020902
Abstrakt:	Background: 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. Methods: 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 . Results: 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. Summary: 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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Xiao, Lian, Zhong, Krishnachaitanya, Cong, Dashwood, Savidge, Powell, Liu and Li.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu