TY - JOUR AU - Langer, Victoria AU - Vivi, Eugenia AU - Regensburger, Daniela AU - Winkler, Thomas H. AU - Waldner, Maximilian J. AU - Rath, Timo AU - Schmid, Benjamin AU - Skottke, Lisa AU - Lee, Somin AU - Jeon, Noo Li AU - Wohlfahrt, Thomas AU - Kramer, Viktoria AU - Tripal, Philipp AU - Schumann, Michael AU - Kersting, Stephan AU - Handtrack, Claudia AU - Geppert, Carol I. AU - Suchowski, Karina AU - Adams, Ralf H. AU - Becker, Christoph AU - Ramming, Andreas AU - Naschberger, Elisabeth AU - Britzen-Laurent, Nathalie AU - Stürzl, Michael T1 - IFN-γ drives inflammatory bowel disease pathogenesis through VE-cadherin–directed vascular barrier disruption PY - 2019/11/01/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI124884 VL - 129 IS - 11 UR - https://doi.org/10.1172/JCI124884 SP - 4691 EP - 4707 PB - The American Society for Clinical Investigation ER -