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Cited by 66Inflammatory Bowel DiseaseProtease and Inhibitor MechanismsGastrointestinal motility and disorders

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

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Cheng, Yang, Hall, Tyler R., Xu, Xiao, Yung, Ivy, Souza, Donald, Zheng, Jie, Schiele, Felix, Hoffmann, Matthias +3 more·2022·eBioMedicine
DOI 10.1016/j.ebiom.2021.103758PMC PMC8688562
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Abstract

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 breakdown. Deficiency of uPAR in epithelial cells leads to enhanced EGF/EGFR signalling, a known regulator of epithelial homeostasis and repair. Mice deficient of uPAR display improved intestinal barrier function in vitro and during DSS-induced colitis in vivo. INTERPRETATION: Our findings suggest that blocking uPA-uPAR interaction via pharmacological agents protects the epithelial barrier from inflammation-induced damage, indicating a potential therapeutic target for IBD. FUNDING: The study was funded by Boehringer Ingelheim.

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  • Human intestinal organoid-derived monolayers have been successfully used to study host-pathogen interactions, epithelial barrier function, and various transport processes including secretion of hormones, growth factors, and ions, and absorption of glucose.

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    From Regulation of Enterocyte Brush Border Membrane Primary Na-Absorptive Transporters in Human Intestinal Organoid-Derived Monolayers (2024) · cites this paper as [13]

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Cited by

Sorted by citations

Authors
Cheng, Y., Hall, T. R., Xu, X., Yung, I., Souza, D., Zheng, J., Schiele, F., Hoffmann, M., Mbow, M. L., Garnett, J. P., & Li, J.
Affiliations
  • Boehringer Ingelheim (United States) (US)
  • Boehringer Ingelheim (Germany) (DE)
Corresponding author
Li, Jun
ORCID
Venue
eBioMedicine
Publisher
Elsevier BV
Published
2022-01
Volume
75
Pages
103758
ISSN
2352-3964 (ISSN-L)
DOI
10.1016/j.ebiom.2021.103758
PMC
PMC8688562
OpenAlex
W4200130257
Cited by
66
References
2
Citations by year
2026: 11 · 2025: 21 · 2024: 18 · 2023: 10 · 2022: 6
FWCI
1.25
Type
journal article
Language
en
Open access
Licence
Locations
  • EBioMedicine (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Boehringer Ingelheim
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
Keywords
urokinase, uPAR, urokinase receptor, intestinal epithelial barrier integrity, inflammatory bowel disease, tight junctions, DSS-induced colitis, intestinal organoids, ligand-receptor pairs, therapeutic target
MeSH terms
Animals, Colitis, Disease Models, Animal, Humans, Intestinal Mucosa, Mice, Inbred C57BL, Permeability, Inflammatory Bowel Diseases, Dextran Sulfate, Caco-2 Cells, Tight Junctions, Mice

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