Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3

Abstract

The role of non-parenchymal liver cells as part of the hepatic, innate immune system in the defense against hepatotropic viruses is not well understood. Here, primary human Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells were isolated from liver tissue obtained after tumor resections or liver transplantations. Cells were stimulated with Toll-like receptor 1–9 ligands for 6–24 h. Non-parenchymal liver cells expressed and secreted inflammatory cytokines (IL6, TNF and IL10). Toll-like receptor- and cell type-specific downstream signals included the phosphorylation of NF-κB, AKT, JNK, p38 and ERK1/2. However, only supernatants of TLR3-activated Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells contained type I and type III interferons and mediated an antiviral activity in the interferon-sensitive subgenomic hepatitis C virus replicon system. The antiviral effect could not be neutralized by antibodies against IFNA, IFNB nor IFNL, but could be abrogated using an interferon alpha receptor 2-specific neutralization. Interestingly, TLR3 responsiveness was enhanced in liver sinusoidal endothelial cells isolated from hepatitis C virus-positive donors, compared to uninfected controls. In conclusion, non-parenchymal liver cells are potent activators of the hepatic immune system by mediating inflammatory responses. Furthermore, liver sinusoidal endothelial cells were identified to be hyperresponsive to viral stimuli in chronic hepatitis C virus infection.

Poly(I:C) Induces Distinct Liver Cell Type-Specific Responses in Hepatitis B Virus-Transgenic Mice In Vitro, but Fails to Induce These Signals In Vivo

“…Antiviral TLR signalling in murine [ 10 ] and human [ 13 , 43 ] liver cells is restricted to TLR3 and to some extent to TLR4 [ 10 ]. Wu et al have visualised the anti-HBV effect of TLR3-activated PMH, LSEC, KC and murine dendritic cells [ 10 ].…”

“…Interestingly, in HBV-transgenic mice lacking the HBV surface antigen (HBsAg), an endogenous TLR3-mediated response in a Kupffer cell (KC) has been described [ 11 ]. Furthermore, interferon-related antiviral TLR activity in human parenchymal [ 12 ] and non-parenchymal liver cells [ 13 ] is restricted to TLR3, highlighting its important role in a hepatic antiviral capacity.…”

Oligonucleotide-Based Therapies for Chronic HBV Infection: A Primer on Biochemistry, Mechanisms and Antiviral Effects

“…Innate immunoreactivity driven by PRR within the liver occurs in three main cell types: hepatocytes, liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs) (Figure 4). Within these cell types, oligonucleotide immune reactivity (TLR3/7/8/9) is most predominant in LSECs and KCs (Figure 4) [46][47][48]. PS modification of ASOs and NAPs drives their accumulation primarily in the liver and kidney [49][50][51][52] and is not affected by 2′ ribose modification.…”