Viral and host factors induce macrophage activation and loss of toll-like receptor tolerance in chronic HCV infection
Department of Medicine, Division of Gastroenterology; Department of Medicine, Rheumatology Division
Adult; Case-Control Studies; Endotoxins; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Inflammation; Interferon-gamma; Kupffer Cells; Ligands; Lipopolysaccharides; Macrophage Activation; Macrophages; Male; Middle Aged; Monocytes; NF-kappa B; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptors; Tumor Necrosis Factor-alpha; Viral Core Proteins
Gastroenterology | Hepatology
BACKGROUND and AIMS: Persistent inflammation contributes to progression of liver damage in chronic HCV (cHCV) infection. Repeated exposure to toll-like receptor (TLR) ligands results in tolerance, a protective mechanism aimed at limiting inflammation.
METHODS: Monocytes/macrophages were repeatedly stimulated via proinflammatory cytokine-inducing TLRs and evaluated for activation markers.
RESULTS: Unlike monocytes of controls or patients with nonalcoholic steatohepatitis, the monocytes of cHCV patients were hyperresponsive and failed to show homo- or heterotolerance to TLR ligands, manifested by elevated tumor necrosis factor (TNF)-alpha production. Serum levels of interferon (IFN)-gamma, endotoxin (TLR4 ligand), and HCV core protein (TLR2 ligand) were elevated in cHCV patients suggesting potential mechanisms for in vivo monocyte preactivation. Treatment of normal monocytes with IFN-gamma resulted in loss of tolerance to lipopolysaccharide (LPS) or HCV core protein. Furthermore, we found increased levels of MyD88-IRAK1 complexes and nuclear factor (NF)-kappaB activity both in monocytes of cHCV patients and in normal monocytes that lost TLR tolerance after IFN-gamma + LPS pretreatment. In vitro differentiation of TLR non-tolerant cHCV monocytes into macrophages restored their capacity to exhibit TLR tolerance to LPS and HCV core protein, and this could be reversed by administration of IFN-gamma. cHCV patients exhibited increased TNF-alpha in the circulation and in the liver. In cHCV livers, we found Kupffer cell/macrophage activation indicated by increased CD163 and CD33 expression.
CONCLUSIONS: We identified that host-derived factors (IFN-gamma and endotoxin) and viral factors (HCV core protein) act in tandem to induce and maintain monocyte/macrophage activation, thus favoring persistent inflammation in patients with cHCV infection.
DOI of Published Version
Gastroenterology. 2007 Nov;133(5):1627-36. Epub 2007 Aug 2. Link to article on publisher's site
Dolganiuc A, Norkina O, Kodys K, Catalano D, Bakis G, Marshall C, Mandrekar P, Szabo G. (2007). Viral and host factors induce macrophage activation and loss of toll-like receptor tolerance in chronic HCV infection. Gastroenterology Publications. https://doi.org/10.1053/j.gastro.2007.08.003. Retrieved from https://escholarship.umassmed.edu/gastroenterology_pp/57