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 6

IFN-γ compromises mural cell coverage and VE-cadherin–mediated cell-cell interactions during DSS-induced colitis and human IBD.

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IFN-γ compromises mural cell coverage and VE-cadherin–mediated cell-cell...
(A) Costaining of α-SMA (red) and CD31 (green) in colon tissue of Ifngr2ΔEC (n = 11, in total 783 vessels) and control mice (n = 9, in total 827 vessels) with DSS-colitis (pooled results from 2 independent experiments). Mural cell coverage (α-SMA+) was categorized as negative/weak (arrowheads), moderate, or high (arrows). Scale bar: 25 μm. (B) VE-cadherin (green) colocalization with colonic vessels (CD31, red) of Ifngr2ΔEC and control mice with DSS-colitis (n = 3 each) visualized by 2-photon microscopy. The mean colocalization of Ifngr2ΔEC mice was set to 100%. Data are expressed as box-and-whisker plots. Horizontal bars indicate the median, box borders indicate the 25th and 75th percentiles, and whiskers indicate minimum and maximum values. Scale bar: 25 μm. (C) Human IBD and corresponding uninvolved intestinal tissues (n = 11; 487 vessels in inflamed and 333 vessels in uninvolved regions) were stained for CD31 (red) and VE-cadherin (green). Vessel colocalization with VE-cadherin was categorized as negative/weak, moderate, or high. VL, vessel lumen. Scale bar: 50 μm. (A and C) Nuclei stained by DRAQ5 (blue). χ2 test (A and C) and 2-tailed, unpaired Student’s t test (B) were used (**P < 0.01, ****P < 0.0001).