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IFN-? 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-? 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-? also exerts potent effects on blood vessels. Based on these considerations, we analyzed the vessel-directed pathogenic functions of IFN-? and found that it drives IBD pathogenesis through vascular barrier disruption. Specifically, we show that inhibition of the IFN-? response in vessels by endothelial-specific knockout of IFN-? receptor 2 ameliorates experimentally induced colitis in mice. IFN-? 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-?-mediated intestinal vessel activation in IBD and open new avenues for vascular-directed treatment of this disease.

SUBMITTER: Langer V 

PROVIDER: S-EPMC6819119 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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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 tha  ...[more]

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