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

Langer V, Vivi E, Regensburger D, Winkler T, Waldner M, Rath T, Schmid B, Skottke L, Lee S, Jeon NL, Wohlfahrt T, Kramer V, Tripal P, Schumann M, Kersting S, Handtrack C, Geppert CI, Suchowski K, Adams RH, Becker C, Naschberger E, Britzen-Laurent N, Stürzl M, Ramming A (2019)

Publication Status: Published

Publication Type: Journal article

Publication year: 2019

Journal

Journal of Clinical Investigation American Society for Clinical Investigation

Book Volume: 129

Pages Range: 4691-4707

Journal Issue: 11

DOI: 10.1172/JCI124884

Abstract

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.

Authors with CRIS profile

Victoria Pürzer Professur für Molekulare und Experimentelle Chirurgie Daniela Regensburger Professur für Molekulare und Experimentelle Chirurgie Thomas Winkler Professur für Genetik Maximilian Waldner Lehrstuhl für Innere Medizin I Timo Rath Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Benjamin Schmid Optical Imaging Center Erlangen (OICE) Philipp Tripal Optical Imaging Center Erlangen (OICE) Carol-Immanuel Geppert Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie Christoph Becker Professur für Molekulare Gastroenterologie Elisabeth Naschberger Medizinische Fakultät Nathalie Britzen-Laurent Professur für Molekulare und Experimentelle Chirurgie Michael Stürzl Professur für Molekulare und Experimentelle Chirurgie Andreas Ramming Department of Medicine 3 – Rheumatology and Immunology

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Involved external institutions

Seoul National University (SNU) / 서울대학교 KR Korea, Republic of (KR) Charité - Universitätsmedizin Berlin DE Germany (DE) Roche Deutschland Holding GmbH DE Germany (DE) Max-Planck-Institut für molekulare Biomedizin / Max Planck Institute for Molecular Biomedicine DE Germany (DE)

How to cite

APA:

Langer, V., Vivi, E., Regensburger, D., Winkler, T., Waldner, M., Rath, T.,... Ramming, A. (2019). IFN-γ drives inflammatory bowel disease pathogenesis through VE-cadherin-directed vascular barrier disruption. Journal of Clinical Investigation, 129(11), 4691-4707. https://doi.org/10.1172/JCI124884

MLA:

Langer, Victoria, et al. "IFN-γ drives inflammatory bowel disease pathogenesis through VE-cadherin-directed vascular barrier disruption." Journal of Clinical Investigation 129.11 (2019): 4691-4707.

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