Targeting uPA-uPAR interaction to improve intestinal epithelial barrier integrity in inflammatory bowel disease

作者：Cheng Yang, Tyler R. Hall, Xiao‐Ming Xu, Ivy Yung, Donald Souza, Jie Zheng, Felix Schiele, Matthias Hoffmann, M. Lamine Mbow, James P. Garnett, Jun Li · 发表于：EBioMedicine · 年份：2021 · DOI：10.1016/j.ebiom.2021.103758 · 被引用次数：64 · 研究领域：Barrier Structure and Function Studies、Inflammatory Bowel Disease、Cell Adhesion Molecules Research

BACKGROUND: Loss of intestinal epithelial barrier integrity is a critical component of Inflammatory Bowel Disease (IBD) pathogenesis. Co-expression regulation of ligand-receptor pairs in IBD mucosa has not been systematically studied. Targeting ligand-receptor pairs which are induced in IBD mucosa and function in intestinal epithelial barrier integrity may provide novel therapeutics for IBD. METHODS: We performed transcriptomic meta-analysis on public IBD datasets combined with cell surface protein-protein-interaction (PPI) databases. We explored primary human/mouse intestinal organoids and Caco-2 cells for expression and function studies of uPA-uPAR (prime hits from the meta-analysis). Epithelial barrier integrity was measured by Trans-Epithelial Electrical Resistance (TEER), FITC-Dextran permeability and tight junction assessment. Genetic (CRISPR, siRNA and KO mice) and pharmacological (small molecules, neutralizing antibody and peptide inhibitors) approaches were applied. Mice deficient of uPAR were studied using the Dextran Sulfate Sodium (DSS)-induced colitis model. FINDINGS: The IBD ligand-receptor meta-analysis led to the discovery of a coordinated upregulation of uPA and uPAR in IBD mucosa. Both genes were significantly upregulated during epithelial barrier breakdown in primary intestinal organoids and decreased during barrier formation. Genetic inhibition of uPAR or uPA, or pharmacologically blocking uPA-uPAR interaction protects against cytokine-induced barrier brea...