IFN-γ drives inflammatory bowel disease pathogenesis through VE-cadherin–directed vascular barrier disruption
| Autor: | Michael Stürzl, Daniela Regensburger, Thomas Wohlfahrt, Viktoria Kramer, Noo Li Jeon, Eugenia Vivi, Somin Lee, Victoria Langer, Nathalie Britzen-Laurent, Lisa Skottke, Christoph Becker, Timo Rath, Ralf H. Adams, Karina Suchowski, Andreas Ramming, Benjamin Schmid, Philipp Tripal, Elisabeth Naschberger, Stephan Kersting, Carol Geppert, Claudia Handtrack, Michael Schumann, Thomas Winkler, Maximilian J. Waldner |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 0301 basic medicine Vascular permeability Inflammation Context (language use) Inflammatory bowel disease Pathogenesis Adherens junction Interferon-gamma Mice 03 medical and health sciences 0302 clinical medicine Antigens CD medicine Animals Humans Colitis Aged Mice Knockout business.industry Endothelial Cells Adherens Junctions General Medicine Middle Aged Cadherins Inflammatory Bowel Diseases medicine.disease 030104 developmental biology 030220 oncology & carcinogenesis Imatinib Mesylate Cancer research Female medicine.symptom VE-cadherin business Research Article |
| Zdroj: | Journal of Clinical Investigation. 129:4691-4707 |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci124884 |
| Popis: | Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with rising incidence. Diseased tissues are heavily vascularized. Surprisingly, the pathogenic impact of the vasculature in IBD and the underlying regulatory mechanisms remain largely unknown. IFN-γ is a major cytokine in IBD pathogenesis, but in the context of the disease, it is almost exclusively its immune-modulatory and epithelial cell-directed functions that have been considered. Recent studies by our group demonstrated that IFN-γ also exerts potent effects on blood vessels. Based on these considerations, we analyzed the vessel-directed pathogenic functions of IFN-γ and found that it drives IBD pathogenesis through vascular barrier disruption. Specifically, we show that inhibition of the IFN-γ response in vessels by endothelial-specific knockout of IFN-γ receptor 2 ameliorates experimentally induced colitis in mice. IFN-γ acts pathogenic by causing a breakdown of the vascular barrier through disruption of the adherens junction protein VE-cadherin. Notably, intestinal vascular barrier dysfunction was also confirmed in human IBD patients, supporting the clinical relevance of our findings. Treatment with imatinib restored VE-cadherin/adherens junctions, inhibited vascular permeability, and significantly reduced colonic inflammation in experimental colitis. Our findings inaugurate the pathogenic impact of IFN-γ-mediated intestinal vessel activation in IBD and open new avenues for vascular-directed treatment of this disease. |
| Databáze: | OpenAIRE |
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