Hepatitis C Virus Induced Endothelial Inflammatory Response Depends on the Functional Expression of TNFα Receptor Subtype 2

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.

Effects of early or late prenatal immune activation in mice on behavioral and neuroanatomical abnormalities relevant to schizophrenia in the adulthood

“…Confirming that poly I:C did induce MIA, we observed that white blood cells were significantly decreased 24 h after injection. This is in accordance with Pircher et al (2014). This result could be explained by the proinflammatory effects that the synthetic analogue of viral dsRNA plays on endothelial cells, such as reduction in leukocyte rolling velocity, increase in leukocyte adhesion to the vessel wall, and increased extravasation of leukocytes from the circulation to peritoneal cavity or other tissues conditions tightly implicated in systemic inflammation (Pircher et al, 2014).…”

Macrophage Activation and the Tumor Necrosis Factor Cascade in Hepatitis C Disease Progression Among HIV-Infected Women Participating in the Women's Interagency HIV Study

“…Significantly elevated levels of sTNFR-II were reported in HCV-infected patients with cirrhosis and hepatocellular carcinoma compared to controls and may reflect degree of hepatic inflammation 41,42 . A recent study showed that HCV-induced endothelial inflammatory response depends on the functional expression of TNFR-II 43 . Exactly how the TNF cascade affects HCV disease progression and what triggers of activation of the TNF-cascade in HIV/HCV coinfection are not fully articulated.…”

Early changes in dynamic biomarkers of liver fibrosis in hepatitis C virus-infected patients treated with sofosbuvir

“…HA in its polymeric variants exerts multiple functions, including the regulation of cell adhesion, inflammatory cell recruitment, release of pro-inflammatory cytokines, and cell migration [33]. CHC induces a generalized inflammatory response in the liver, including the sinusoidal endothelium [34]. While the reason for the transient increase in HA at the beginning of antiviral therapy needs further investigation, one could speculate that the reconstitution of the Th1 T cell response to HCV by highly efficient therapy affects not only the extracellular matrix, including its remodelling and degradation, which may be reflected by the rise of HA in serum, but also transiently increases the inflammatory infiltrate.…”