Hepatitis C virus induced endothelial inflammatory response depends on the functional expression of TNFα receptor subtype 2

PLoS One. 2014 Nov 24;9(11):e113351. doi: 10.1371/journal.pone.0113351. eCollection 2014.

Abstract

In hepatitis C virus (HCV) infection, morbidity and mortality often result from extrahepatic disease manifestations. We provide evidence for a role of receptors of the innate immune system in virally induced inflammation of the endothelium in vitro and in vivo. Corresponding to the in vitro finding of an HCV-dependent induction of proinflammatory mediators in endothelial cells, mice treated with poly (I:C) exhibit a significant reduction in leukocyte rolling velocity, an increase in leukocyte adhesion to the vessel wall and an increased extravasation of leukocytes. HCV directly promotes activation, adhesion and infiltration of inflammatory cells into the vessel wall by activation of endothelial viral receptors. Poly (I:C) induces the expression of TLR3 in vivo and hereby allows for amplification of all of the aforementioned responses upon viral infection. Proinflammatory effects of viral RNA are specifically mediated by TLR3 and significantly enhanced by tumor necrosis factor alpha (TNFα). HCV-RNA induces the endothelial expression of TNFα and TNFα receptor subtype 2 and we provide evidence that leucocyte adhesion and transmigration in response to activation of viral RNA receptors seem to depend on expression of functional TNFR2. Our results demonstrate that endothelial cells actively participate in immune mediated vascular inflammation caused by viral infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cytokines / genetics
  • Cytokines / metabolism*
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism
  • Endothelial Cells / metabolism
  • Endothelial Cells / virology*
  • Gene Expression / drug effects
  • Hepacivirus / genetics
  • Hepacivirus / physiology*
  • Host-Pathogen Interactions
  • Humans
  • Interferon-Induced Helicase, IFIH1
  • Leukocyte Rolling / drug effects
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Poly I-C / pharmacology
  • RNA Interference
  • Receptors, Tumor Necrosis Factor, Type II / genetics
  • Receptors, Tumor Necrosis Factor, Type II / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Toll-Like Receptor 3 / genetics
  • Toll-Like Receptor 3 / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Cytokines
  • Receptors, Tumor Necrosis Factor, Type II
  • TLR3 protein, human
  • TNFRSF1B protein, human
  • Toll-Like Receptor 3
  • Tumor Necrosis Factor-alpha
  • IFIH1 protein, human
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1
  • Poly I-C

Grants and funding

This work was supported by grant WO 1716/1-1 from the Deutsche Forschungsgemeinschaft (DFG), a grant from the Else Kröner-Fresenius-Stiftung and the Wilhelm-Vaillant-Stiftung to MW and a grant from The Friedrich Baur Stiftung to JP. This paper contains part of Thomas Czermak's and Jonathan Nadjiri's doctoral thesis, which was approved by the medical faculty of the Ludwig Maximilians University Munich. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.