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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

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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 5

The intestinal vasculature is characterized by IFN-γ–mediated barrier dysfunction in murine DSS-induced colitis and human IBD.

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The intestinal vasculature is characterized by IFN-γ–mediated barrier dy...
(A–D) Seventy-kDa FITC-dextran (10 mg/mL) was injected i.v. in mice with acute and chronic DSS-colitis. Accumulation in intestinal crypts (arrows) indicates vessel permeability, calculated as the ratio of FITC signal inside the crypts over the total FITC signal. Vessel permeability was reduced in Ifngr2ΔEC (n = 4) (A) and Ifngr2iΔEC (n = 7) mice (B) compared with control mice (n = 4 and 7, respectively) during acute (A and B) and chronic colitis (C; 4 Ifngr2ΔEC vs. 5 control). For quantitative evaluation, 10–12 crypts were analyzed per mouse. Scale bars: 50 μm. (D) Control mice with αVEGF treatment (150 μg/mouse, n = 8) and Ifngr2ΔEC mice (n = 8) showed reduced vascular permeability in contrast to control mice treated with isotype antibody (150 μg/mouse, n = 7). Scale bar: 50 μm. For quantitative evaluation, 10 crypts per mouse were analyzed. Pooled results from 2 independent experiments are shown. (E) Human IBD patients with active disease (n = 8) or remission (n = 7) or control patients without IBD (n = 3) underwent pCLE. Fluorescein accumulation in intestinal crypts (arrows) indicates vessel permeability, calculated as the ratio of fluorescein signal inside the crypts over total fluorescein signal. Vessel permeability was increased in active disease (10 crypts per patient). Scale bar: 20 μm. Representative pictures are shown. Quantitative evaluations (right side of each panel) are shown as box-and-whisker plots (horizontal bars, median; box borders, 25th and 75th percentiles; whiskers, minimum and maximum values; A–D) or means ± SD (E). Mann-Whitney U test (A–C), Kruskal-Wallis test followed by Dunn’s post hoc test (D), and 1-way ANOVA followed by Tukey’s post hoc test (D) were used to determine statistical significance (***P < 0.001, ****P < 0.0001).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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