PAI-1 augments mucosal damage in colitis

• Published in: Science translational medicine 2019-03, Vol.11 (482)
• Main Authors: Kaiko, Gerard E, Chen, Feidi, Lai, Chin-Wen, Chiang, I-Ling, Perrigoue, Jacqueline, Stojmirović, Aleksandar, Li, Katherine, Muegge, Brian D, Jain, Umang, VanDussen, Kelli L, Goggins, Bridie J, Keely, Simon, Weaver, Jessica, Foster, Paul S, Lawrence, Daniel A, Liu, Ta-Chiang, Stappenbeck, Thaddeus S
• Format: Article
• Language: English
• Subjects: Animals; Biological Factors - pharmacology; Biological Factors - therapeutic use; Blood Coagulation; Cell Proliferation - drug effects; Citrobacter - drug effects; Coagulation; Colitis; Colitis - immunology; Colitis - metabolism; Colitis - microbiology; Colitis - pathology; Colon; Colon - pathology; Cytokines - metabolism; Epithelial cells; Epithelium; Fibrin; Gene expression; Inflammation - pathology; Inflammatory bowel diseases; Inflammatory Bowel Diseases - blood; Inflammatory Bowel Diseases - drug therapy; Inflammatory Bowel Diseases - pathology; Interleukin-17 - metabolism; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Intestine; Mice; Mucosa; Plasminogen Activator Inhibitor 1 - metabolism; Plasminogen activator inhibitors; Severity of Illness Index; Small Molecule Libraries - pharmacology; t-Plasminogen activator; Th17 Cells - immunology; Tissue Plasminogen Activator - metabolism; Transcription, Genetic; Transforming Growth Factor beta - metabolism; Tumor necrosis factor
• ISSN: 1946-6234; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.aat0852

There is a major unmet clinical need to identify pathways in inflammatory bowel disease (IBD) to classify patient disease activity, stratify patients that will benefit from targeted therapies such as anti-tumor necrosis factor (TNF), and identify new therapeutic targets. In this study, we conducted global transcriptome analysis to identify IBD-related pathways using colon biopsies, which highlighted the coagulation gene pathway as one of the most enriched gene sets in patients with IBD. Using this gene-network analysis across 14 independent cohorts and 1800 intestinal biopsies, we found that, among the coagulation pathway genes, plasminogen activator inhibitor-1 (PAI-1) expression was highly enriched in active disease and in patients with IBD who did not respond to anti-TNF biologic therapy and that PAI-1 is a key link between the epithelium and inflammation. Functionally, PAI-1 and its direct target, the fibrinolytic protease tissue plasminogen activator (tPA), played an important role in regulating intestinal inflammation. Intestinal epithelial cells produced tPA, which was protective against chemical and mechanical-mediated colonic injury in mice. In contrast, PAI-1 exacerbated mucosal damage by blocking tPA-mediated cleavage and activation of anti-inflammatory TGF-β, whereas the inhibition of PAI-1 reduced both mucosal damage and inflammation. This study identifies an immune-coagulation gene axis in IBD where elevated PAI-1 may contribute to more aggressive disease.