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J Clin Invest. 2019 Sep 30. pii: 124884. doi: 10.1172/JCI124884. [Epub ahead of print]

IFN-γ drives inflammatory bowel disease pathogenesis through VE-cadherin-directed vascular barrier disruption.

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Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery, University Medical Center Erlangen.
Division of Genetics, Nikolaus-Fiebiger-Center of Molecular Medicine.
Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, University Medical Center Erlangen, and.
Optical Imaging Centre, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
Program for Bioengineering, School of Engineering, Seoul National University, Seoul, Republic of Korea.
Department of Internal Medicine 3, Rheumatology and Immunology, University Medical Center Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
Medical Clinic I, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Department of Surgery and.
Institute of Pathology, University Medical Center Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
Discovery Oncology, Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany.
Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany.


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.


Cytokines; Gastroenterology; Inflammatory bowel disease; Vascular Biology; endothelial cells

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