IFN-γ drives inflammatory bowel disease pathogenesis through VE-cadherin–directed vascular barrier disruption
Victoria Langer, … , Nathalie Britzen-Laurent, Michael Stürzl
Victoria Langer, … , Nathalie Britzen-Laurent, Michael Stürzl
Published September 30, 2019
Citation Information: J Clin Invest. 2019;129(11):4691-4707. https://doi.org/10.1172/JCI124884.
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Research Article Gastroenterology Vascular biology

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

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

Victoria Langer, Eugenia Vivi, Daniela Regensburger, Thomas H. Winkler, Maximilian J. Waldner, Timo Rath, Benjamin Schmid, Lisa Skottke, Somin Lee, Noo Li Jeon, Thomas Wohlfahrt, Viktoria Kramer, Philipp Tripal, Michael Schumann, Stephan Kersting, Claudia Handtrack, Carol I. Geppert, Karina Suchowski, Ralf H. Adams, Christoph Becker, Andreas Ramming, Elisabeth Naschberger, Nathalie Britzen-Laurent, Michael Stürzl

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Figure 8

Treatment with imatinib restores vascular barrier function and reduces DSS-induced inflammation.

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Treatment with imatinib restores vascular barrier function and reduces D...
(A) Imatinib (0.01 μg/mL) reduced IFN-γ–induced (100 U/mL) endothelial cell (MIEC) permeability in vitro; values are normalized to untreated cells. (B) Immunofluorescence staining of VE-cadherin (green), counterstained by DRAQ5 (blue), in MIECs treated with IFN-γ (100 U/mL), imatinib (0.01 μg/mL) plus IFN-γ, or imatinib alone or left untreated. Arrows indicate linear VE-cadherin pattern at cell-cell contacts; asterisks mark internalization. Scale bar: 25 μm. (C–F) Control mice received imatinib (n = 11) orally daily during the course of DSS-colitis or PBS only (n = 10) and were compared with Ifngr2ΔEC mice receiving the same treatment (n = 3, imatinib; n = 4, PBS). (C) In vivo permeability of colonic vessels was assessed by i.v. injection of 70-kDa FITC-dextran (10 mg/mL). Accumulation in intestinal crypts (arrows) indicates vessel permeability, calculated as the ratio of FITC signal inside the crypts over the total FITC signal in percent (10 crypts per mouse). Scale bar: 50 μm. Treatment with imatinib reduced the severity of DSS-colitis in control mice evaluated by endoscopy (D), colon length (E), and histologic examination by H&E staining (F; scale bar: 100 μm). (A and B) One representative of 3 independent experiments is depicted. Quantitative evaluations are shown as box-and-whisker plots (A and C) (horizontal bars, median; box borders, 25th and 75th percentiles; whiskers, minimum and maximum values) or means ± SD (D and E). All graphs are means ± SD. One-way ANOVA followed by Tukey’s post hoc test (A, D, and E) and Kruskal-Wallis test followed by Dunn’s post hoc test (C) were used for statistical evaluation (*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001). For genotypes of respective mice, see Supplemental Figure 1E.