Interferon-gamma-impaired vascular barrier function contributes to IBD pathogenesis

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders consisting of the two major forms Crohn`s disease (CD) and ulcerative colitis (UC). Although IBD are of rising incidence, their pathogenesis is not fully understood yet. Even though IBD are characterized by an extensive intestinal vascularization, the pathogenic impact of the vasculature in IBD and its underlying regulatory mechanisms remain largely unknown. One of the most highly upregulated cytokines during IBD is Interferon-gamma (IFN-g). As yet, its role in IBD pathogenesis has been attributed to its immune modulatory and epithelial cell-directed effects. Interestingly, IFN-g has been shown to exert potent functions on endothelial cells as well. Therefore, we analyzed endothelial-directed effects of IFN-g in the context of IBD. Using a mouse model based on the endothelial-specific knockout of the IFN-g-receptor 2 (Ifngr2EndoC), we showed that loss of the vascular IFN-g response ameliorates the course of dextran sulfate sodium (DSS)-induced colitis in mice, while increasing angiogenesis, as confirmed in vitro and ex vivo. However, blockade of VEGF, and thereby inhibition of angiogenesis, also resulted in a milder course of DSS-colitis in mice, suggesting that the angiogenic activity is not the most crucial vascular factor for IBD pathogenesis. On the contrary, the breakdown of the endothelial barrier function by IFN-g was shown to be of pathogenic relevance in murine colitis. Both Ifngr2EndoC and anti-VEGF-A-treated mice had a reduced intestinal vascular permeability as shown by intra-vital imaging in comparison to control mice during DSS-colitis, accompanied by a milder intestinal inflammation. In addition, IFN-g reduced vessel coverage with mural cells in DSS-colitis, which is commonly associated with a reduced stability of the endothelial barrier. A disrupted vascular barrier integrity was confirmed by confocal laser endomicroscopy in human IBD patients. We demonstrated that IFN-g disrupts membranous VE-cadherin integrity causing increased endothelial permeability in vitro. Impairment of VE-cadherin junctions by IFN-g was confirmed in vivo by two-photon microscopy in mice with DSS-colitis. Furthermore, we showed that human IBD patients were characterized by a loss of VE-cadherin junction integrity in inflamed intestinal areas. Additionally, we found that imatinib, a receptor tyrosine kinase inhibitor recently shown to block vascular permeability, restored VE-cadherin junctions leading to a reduction of IFN-g-induced endothelial permeability in vitro and in vivo and a milder course of DSS-colitis in mice. In summary, this work identified a new pathogenic function of IFN-g in IBD, comprising the breakdown of the intestinal vascular barrier function by impairment of VE-cadherin mediated junctions. The results may be of high clinical relevance for new vascular-directed therapy approaches in IBD.