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.
Highlights
More than 170 million people worldwide are chronically infected with the hepatitis C virus (HCV), which is responsible for over 1 million deaths resulting from cirrhosis and primary liver cancers [1]
In order to test the effect of ligand binding on the expression of viral receptors, Human microvascular endothelial cells (HMEC) were stimulated with poly (I:C) (10 mg/ml) mimicking viral RNA for different time intervals (3, 6, 9, 12, 24, 48 hours)
The cytokine combination led to an enhanced expression of the viral receptors TLR3, retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5); the effect of poly (I:C) on the expression of TLR3 and MDA5 was amplified in cells pretreated with proinflammatory cytokines. (Figure 1J–L)
Summary
More than 170 million people worldwide are chronically infected with the hepatitis C virus (HCV), which is responsible for over 1 million deaths resulting from cirrhosis and primary liver cancers [1]. We have previously shown the impact of activation of viral receptors of the innate immune system, TLR3, on HCV-associated glomerulonephritis [8, 9, 10]. TLR recognize molecular patterns associated with microbial pathogens and induce an immune response [11]. We show that both poly (I:C) and HCV-RNA isolated from patients infected with the Hepatitis C virus induce the endothelial expression of proinflammatory cytokines, chemokines and type I interferons as well as adhesion molecules. These effects of viral RNA on endothelial cells are mediated by TLR3. We demonstrate an immunomodulatory role of the TNFa/TNF receptor system in HCV-associated vasculitis with a potential impact on the development of new therapeutic strategies
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