IFN-γ drives inflammatory bowel disease pathogenesis through VE-cadherin-directed vascular barrier disruption

J Clin Invest. 2019 Nov 1;129(11):4691-4707. doi: 10.1172/JCI124884.

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.

Keywords: Cytokines; Gastroenterology; Inflammatory bowel disease; Vascular Biology; endothelial cells.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Adherens Junctions / genetics
  • Adherens Junctions / immunology
  • Adherens Junctions / pathology
  • Adult
  • Aged
  • Animals
  • Antigens, CD* / genetics
  • Antigens, CD* / immunology
  • Cadherins* / genetics
  • Cadherins* / immunology
  • Endothelial Cells* / immunology
  • Endothelial Cells* / pathology
  • Female
  • Humans
  • Imatinib Mesylate / administration & dosage*
  • Inflammatory Bowel Diseases* / drug therapy
  • Inflammatory Bowel Diseases* / genetics
  • Inflammatory Bowel Diseases* / immunology
  • Inflammatory Bowel Diseases* / pathology
  • Interferon-gamma* / genetics
  • Interferon-gamma* / immunology
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged

Substances

  • Antigens, CD
  • Cadherins
  • IFNG protein, human
  • IFNG protein, mouse
  • cadherin 5
  • Interferon-gamma
  • Imatinib Mesylate

Grant support

no number available