Toll‐like receptor‐induced innate immune responses in non‐parenchymal liver cells are cell type‐specific

Abstract

Summary Little is known of how the Toll‐like receptor (TLR) system can modulate the function of non‐parenchymal liver cells (NPC) as a major component of the innate and adaptive immune system of the liver. To investigate the diversification of TLR signalling pathways in NPC, we isolated Kupffer cells (KC) and liver sinusoidal endothelial cells (LSEC) from wild‐type C57BL/6 mice and examined their responses to TLR1 to TLR9 agonists. The data show that KC respond to all TLR ligands by producing tumour necrosis factor‐α (TNF‐α) or interleukin‐6 (IL‐6), to TLR3 and TLR4 ligands only by producing interferon‐β (IFN‐β), to TLR1 and TLR8 ligands by significantly up‐regulating major histocompatibility complex (MHC) class II and costimulatory molecules, and to TLR1, ‐2, ‐4 and ‐6 ligands by inducing high levels of T‐cell proliferation and IFN‐γ production in the mixed lymphocyte reaction (MLR). Similarly, LSEC respond to TLR1 to ‐4, ‐6, ‐8 and ‐9 ligands by producing TNF‐α, to TLR3 and ‐4 ligands by producing IL‐6, and to TLR3 ligands by producing IFN‐β. Interestingly, despite significant up‐regulation of MHC class II and co‐stimulatory molecules in response to TLR8 ligands, LSEC stimulated by TLR1, ‐2 or ‐6 could stimulate allogeneic T cells as assessed by MLR. By contrast, myeloid dendritic cells, used as positive control for classical antigen‐presenting cells, respond to TLR1, ‐2, ‐4 and ‐9 ligands by both up‐regulation of CD40 and activation of allogeneic T cells. In conclusion, NPC display a restricted TLR‐mediated activation profile when compared with ‘classical’ antigen‐presenting cells which may, at least in part, explain their tolerogenic function in the liver.

Poly(I:C) Treatment Leads to Interferon-Dependent Clearance of Hepatitis B Virus in a Hydrodynamic Injection Mouse Model

“…In our study, a high dose of poly(I:C) (50 g) failed to achieve better antiviral effects than the intermediate dose of 20 g. We have previously shown that the poly(I:C) stimulation of innate immune responses in LSEC and Kupffer cells is dose dependent: high levels of cytokine production and allogeneic T-cell proliferation were found at a dose of 100 g/ml but not at the higher dose of 200 g/ml (26). Other studies have suggested that an excessive amount of poly(I:C) may produce a response spectrum unsuitable for viral clearance, such as transactivating p63 (Tap63␣)-dependent apoptosis (27), activation of intracellular negative regulatory molecules, including A20, tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R), and ubiquitin 1 (28); and type I IFN-dependent exhaustion of memory T cells (29,30) and dendritic cells (DCs) (31).…”

Hepatitis B Virus Nucleocapsid but Not Free Core Antigen Controls Viral Clearance in Mice

“…On the other hand, HBV also evolves to counteract the host innate defense system. The TLR-mediated antiviral activity, for example, was inhibited by HBV (33). Recently, HBV pol and X protein (HBx) were shown to modulate innate immune signaling (16,29,30,36).…”

Tissue macrophages suppress viral replication and prevent severe immunopathology in an interferon-I-dependent manner in mice

“…The inability of hepatocytes to respond to IFN-I could be explained by the finding that hepatocytes failed to express significant levels of messenger RNA encoding IFNAR and downstream signaling molecules compared with macrophages. Liver endothelial cells are equipped with Toll-like receptors and are involved in the antiviral innate immune response, 34,35 including uptake of serum particles. 15 In addition to cytokine production, liver sinusoid endothelial cells show a strong antiviral response to IFN-I, 34,36 which could suppress virus replication 37 ; however, whether this is of benefit for a systemic virus infection remains to be studied.…”