期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 129, 期 11, 页码 4691-4707出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI124884
关键词
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资金
- German Research Foundation (DFG) [KFO 257, FOR 2438, SFB/TRR241, BR 5196/2-1]
- Interdisciplinary Center for Clinical Research (IZKF) of the Clinical Center Erlangen [D28]
- W. Lutz Stiftung
- Forschungsstiftung Medizin am Universitatsklinikum Erlangen
- National Research Foundation of Korea [2016H1A2A1907378] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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-gamma 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-gamma also exerts potent effects on blood vessels. Based on these considerations, we analyzed the vessel-directed pathogenic functions of IFN-gamma and found that it drives IBD pathogenesis through vascular barrier disruption. Specifically, we show that inhibition of the IFN-gamma response in vessels by endothelial-specific knockout of IFN-gamma receptor 2 ameliorates experimentally induced colitis in mice. IFN-gamma 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-gamma-mediated intestinal vessel activation in IBD and open new avenues for vascular-directed treatment of this disease.
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