Activated macrophages promote hepatitis C virus entry in a tumor necrosis factor-dependent manner

Abstract

Macrophages are critical components of the innate immune response in the liver. Chronic hepatitis C is associated with immune infiltration and the infected liver shows a significant increase in total macrophage numbers; however, their role in the viral life cycle is poorly understood. Activation of blood-derived and intrahepatic macrophages with a panel of Toll-like receptor agonists induce soluble mediators that promote hepatitis C virus (HCV) entry into polarized hepatoma cells. We identified tumor necrosis factor α (TNF-α) as the major cytokine involved in this process. Importantly, this effect was not limited to HCV; TNF-α increased the permissivity of hepatoma cells to infection by Lassa, measles and vesicular stomatitis pseudoviruses. TNF-α induced a relocalization of tight junction protein occludin and increased the lateral diffusion speed of HCV receptor tetraspanin CD81 in polarized HepG2 cells, providing a mechanism for their increased permissivity to support HCV entry. High concentrations of HCV particles could stimulate macrophages to express TNF-α, providing a direct mechanism for the virus to promote infection. Conclusion: This study shows a new role for TNF-α to increase virus entry and highlights the potential for HCV to exploit existing innate immune responses in the liver to promote de novo infection events. (Hepatology 2014;59:1320-1330)

Role of apoptotic hepatocytes in HCV dissemination: regulation by acetaldehyde

“…AB also may induce inflammation by programming liver macrophages (Kupffer cells) toward a proinflammatory phenotype. This, in turn, would promote the uptake of virus by hepatocytes (16) and finally contribute to cirrhosis/HCC development (32). The regulation of a cytokine profile of dendritic cells phagocytosed HCV ϩ AB was reported before (59).…”

Mechanism of Kupffer cells in hepatitis infected by hepatitis B and C virus

“…4,5 However, KCs turned to secrete more cytokines like IL-12, and tumor necrosis factor (TNF) with the ligating of TLR4 and some other TLRs. 6 The weak ability of KCs to produce cytokines might be related to the immunity tolerance in the homeostasis in-vivo.…”

“…As some study reported, KCs could produce various pro-fibrinogenic factors, like ROS, and some cytokines such as IL-6, TNF, IL-1, PDGF and TGF-β. 6,16,18 In adittion, certain enzymes are produced by KCs, covering collagenase and metalloenzyme, which could accelerate the fibrosis via the disturbance of steady state in-vivo. 7 Nevertheless, enzymes abovementioned are non-specific of KCs.…”

“…The fact that LPS could promote KCs to produce TNF could indirectly facilitates the HCV infenction of liver. 6 KCs could kill the infected cells in various ways. KCs would activate the natural killer (NK) and natural killer T (NKT) by secreting cytokines.…”

Pro-inflammatory cytokines promote viral replication and cell cycle mediators in arenavirus-induced hepatitis.

“…Furthermore, Fletcher et al showed that with increasing concentrations of TNF-α (i.e. 10, 100, 1000 ng/mL) there was a correlated TNFdependent increase in hepatitis c virus (HCV) and LASV-psuedotyped-particle virus infectivity in polarized HepG2 [77]. However, another group using Huh7 human hepatoma cells found TNF-α stimulation (at physiologically low concentration) alone or in combination with IFN did not positively or negatively impact replication of LASV or LCMV-WE [78].…”