Immune Liver Research Articles

Superior protection in a relapsing Plasmodium cynomolgi rhesus macaque model by a chemoprophylaxis with sporozoite immunization regimen with atovaquone-proguanil followed by primaquine

BackgroundTo gain a deeper understanding of protective immunity against relapsing malaria, this study examined sporozoite-specific T cell responses induced by a chemoprophylaxis with sporozoite (CPS) immunization in a relapsing Plasmodium cynomolgi rhesus macaque model.MethodsThe animals received three CPS immunizations with P. cynomolgi sporozoites, administered by mosquito bite, while under two anti-malarial drug regimens. Group 1 (n = 6) received artesunate/chloroquine (AS/CQ) followed by a radical cure with CQ plus primaquine (PQ). Group 2 (n = 6) received atovaquone-proguanil (AP) followed by PQ. After the final immunization, the animals were challenged with intravenous injection of 104P. cynomolgi sporozoites, the dose that induced reliable infection and relapse rate. These animals, along with control animals (n = 6), were monitored for primary infection and subsequent relapses. Immunogenicity blood draws were done after each of the three CPS session, before and after the challenge, with liver, spleen and bone marrow sampling and analysis done after the challenge.ResultsGroup 2 animals demonstrated superior protection, with two achieving protection and two experiencing partial protection, while only one animal in group 1 had partial protection. These animals displayed high sporozoite-specific IFN-γ T cell responses in the liver, spleen, and bone marrow after the challenge with one protected animal having the highest frequency of IFN-γ+ CD8+, IFN-γ+ CD4+, and IFN-γ+ γδ T cells in the liver. Partially protected animals also demonstrated a relatively high frequency of IFN-γ+ CD8+, IFN-γ+ CD4+, and IFN-γ+ γδ T cells in the liver. It is important to highlight that the second animal in group 2, which experienced protection, exhibited deficient sporozoite-specific T cell responses in the liver while displaying average to high T cell responses in the spleen and bone marrow.ConclusionsThis research supports the notion that local liver T cell immunity plays a crucial role in defending against liver-stage infection. Nevertheless, there is an instance where protection occurs independently of T cell responses in the liver, suggesting the involvement of the liver's innate immunity. The relapsing P. cynomolgi rhesus macaque model holds promise for informing the development of vaccines against relapsing P. vivax.

Triptolide Induces Liver Injury by Regulating Macrophage Recruitment and Polarization via the Nrf2 Signaling Pathway.

Triptolide (TP) has limited usage in clinical practice due to its side effects and toxicity, especially liver injury. Hepatic macrophages, key player of liver innate immunity, were found to be recruited and activated by TP in our previous study. The nuclear factor-erythroid-2-related factor 2 (Nrf2) pathway exerts a protective role in TP-induced liver damage, but its effect on the functions of hepatic macrophage has not been elucidated. Here, we determined whether TP can regulate the recruitment and polarization of hepatic macrophages by inhibiting Nrf2 signaling cascade. Our results demonstrated that TP inhibited the Nrf2 signaling pathway in hepatic macrophages. The changes in hepatic macrophages were responsible for the increased susceptibility toward inflammatory stimuli, and hence, TP pretreatment could induce severe liver damage upon the stimulation of a nontoxic dose of lipopolysaccharides. In addition, the Nrf2 agonist protected macrophages from TP-induced toxicity and Nrf2 deficiency significantly aggravated liver injury by enhancing the recruitment and M1 polarization of hepatic macrophages. This study suggests that Nrf2 pathway-mediated hepatic macrophage polarization plays an essential role in TP-induced liver damage, which can serve as a potential therapeutic target for preventing hepatotoxicity induced by TP.

Response of Human Liver Tissue to Innate Immune Stimuli.

Precision-cut human liver slice cultures (PCLS) have become an important alternative immunological platform in preclinical testing. To further evaluate the capacity of PCLS, we investigated the innate immune response to TLR3 agonist (poly-I:C) and TLR4 agonist (LPS) using normal and diseased liver tissue. Pathological liver tissue was obtained from patients with active chronic HCV infection, and patients with former chronic HCV infection cured by recent Direct-Acting Antiviral (DAA) drug therapy. We found that hepatic innate immunity in response to TLR3 and TLR4 agonists was not suppressed but enhanced in the HCV-infected tissue, compared with the healthy controls. Furthermore, despite recent HCV elimination, DAA-cured liver tissue manifested ongoing abnormalities in liver immunity: sustained abnormal immune gene expression in DAA-cured samples was identified in direct ex vivo measurements and in TLR3 and TLR4 stimulation assays. Genes that were up-regulated in chronic HCV-infected liver tissue were mostly characteristic of the non-parenchymal cell compartment. These results demonstrated the utility of PCLS in studying both liver pathology and innate immunity.

How to get away with liver innate immunity? A viruses' tale.

In their never-ending quest towards persistence within their host, hepatitis viruses have developed numerous ways to counteract the liver innate immunity. This review highlights the different and common mechanisms employed by these viruses to (i) establish in the liver (passive entry or active evasion from immune recognition) and (ii) actively inhibit the innate immune response (ie modulation of pattern recognition receptor expression and/or signalling pathways, modulation of interferon response and modulation of immune cells count or phenotype).

The Antidepressant Mirtazapine Activates HepaticMacrophages, Facilitating Pathogen Clearance While Limiting Tissue Damage in Mice.

Background and AimsMirtazapine is an atypical antidepressant with antagonist activity for serotonin and histamine receptors. Clinical and experimental evidence suggests that, in addition to treating depression, mirtazapine also alters liver innate immunity and suppresses immune-driven hepatic macrophage activation. Liver macrophages, Kupffer cells, represent the largest collection of fixed macrophages in the body and are critical in regulating hepatic immunity. In addition to their capacity to regulate inflammation, Kupffer cells are key sentinels for clearing blood-borne pathogens, preventing their dissemination within the body. This process involves pathogen capture, phagocytosis, and activation-induced killing via reactive oxygen species (ROS) production. Therefore, we speculated that mirtazapine might adversely alter Kupffer cell pathogen-associated activation and killing.MethodsMice were treated with mirtazapine and time-dependent changes in Kupffer cells were characterized using intravital microscopy. Macrophage and neutrophil responses, bacterial dissemination, and liver damage were assessed following i.v. infection with a pathogenic strain of S. aureus.ResultsMirtazapine rapidly (within 1.5 h) activates Kupffer cells, indicated by a loss of elongated shape with cellular rounding. However, this shape change did not result in impaired pathogen capture function, and, in fact, generated enhanced ROS production in response to S. aureus-induced sepsis. Neutrophil dynamics were altered with reduced cellular recruitment to the liver following infection. Bacterial dissemination post-intravenous administration was not altered by mirtazapine treatment; however, hepatic abscess formation was significantly reduced.ConclusionsMirtazapine rapidly activates Kupffer cells, associated with preserved bacterial capture functions and enhanced ROS generation capacity. Moreover, these changes in Kupffer cells were linked to a beneficial reduction in hepatic abscess size. In contrast to our initial speculation, mirtazapine may have beneficial effects in sepsis and warrants further exploration.

Chenopodium Quinoa and Salvia Hispanica Provide Immunonutritional Agonists to Ameliorate Hepatocarcinoma Severity under a High-Fat Diet.

Complex interactions between immunonutritional agonist and high fat intake (HFD), the immune system and finally gut microbiota are important determinants of hepatocarcinoma (HCC) severity. The ability of immunonutritional agonists to modulate major aspects such as liver innate immunity and inflammation and alterations in major lipids profile as well as gut microbiota during HCC development is poorly understood. 1H NMR has been employed to assess imbalances in saturated fatty acids, MUFA and PUFA, which were associated to variations in iron homeostasis. These effects were dependent on the botanical nature (Chenopodium quinoa vs. Salvia hispanica L.) of the compounds. The results showed that immunonutritional agonists’ promoted resistance to hepatocarcinogenesis under pro-tumorigenic inflammation reflected, at a different extent, in increased proportions of F4/80+ cells in injured livers as well as positive trends of accumulated immune mediators (CD68/CD206 ratio) in intestinal tissue. Administration of all immunonutritional agonists caused similar variations of fecal microbiota, towards a lower obesity-inducing potential than animals only fed a HFD. Modulation of Firmicutes to Bacteroidetes contents restored the induction of microbial metabolites to improve epithelial barrier function, showing an association with liver saturated fatty acids and the MUFA and PUFA fractions. Collectively, these data provide novel findings supporting beneficial immunometabolic effects targeting hepatocarcinogenesis, influencing innate immunity within the gut-liver axis, and providing novel insights into their immunomodulatory activity.

The Bile Acid Receptor GPBAR1 Modulates CCL2/CCR2 Signaling at the Liver Sinusoidal/Macrophage Interface and Reverses Acetaminophen-Induced Liver Toxicity.

Drug-induced liver injury caused by acetaminophen (acetyl-para-aminophenol [APAP]) is the main cause of acute liver failure and liver transplantation in several Western countries. Whereas direct toxicity exerted by APAP metabolites is a key determinant for early hepatocytes injury, the recruitment of cells of innate immunity exerts a mechanistic role in disease progression, determining the clinical outcomes. GPBAR1 is a G protein-coupled receptor for secondary bile acids placed at the interface between liver sinusoidal cells and innate immunity. In this report, using genetic and pharmacological approaches, we demonstrate that whereas Gpbar1 gene deletion worsens the severity of liver injury, its pharmacological activation by 6β-ethyl-3a,7b-dihydroxy-5b-cholan-24-ol rescues mice from liver injury caused by APAP. This protective effect was supported by a robust attenuation of liver recruitment of monocyte-derived macrophages and their repolarization toward an anti-inflammatory phenotype. Macrophage depletion by gadolinium chloride pretreatment abrogated disease development, whereas their reconstitution by spleen-derived macrophage transplantation restored the sensitivity to APAP in a GPBAR1-dependent manner. RNA sequencing analyses demonstrated that GPBAR1 agonism modulated the expression of multiple pathways, including the chemokine CCL2 and its receptor, CCR2. Treating wild-type mice with an anti-CCL2 mAb attenuated the severity of liver injury. We demonstrated that negative regulation of CCL2 production by GPBAR1 agonism was promoter dependent and involved FOXO1. In conclusion, we have shown that GPBAR1 is an upstream modulator of CCL2/CCR2 axis at the sinusoidal cell/macrophage interface, providing a novel target in the treatment of liver damage caused by APAP.

Liver sinusoidal endothelial cells contribute to the uptake and degradation of entero bacterial viruses

The liver is constantly exposed to dietary antigens, viruses, and bacterial products with inflammatory potential. For decades cellular uptake of virus has been studied in connection with infection, while the few studies designed to look into clearance mechanisms focused mainly on the role of macrophages. In recent years, attention has been directed towards the liver sinusoidal endothelial cells (LSECs), which play a central role in liver innate immunity by their ability to scavenge pathogen- and damage-associated molecular patterns. Every day our bodies are exposed to billions of gut-derived pathogens which must be efficiently removed from the circulation to prevent inflammatory and/or immune reactions in other vascular beds. Here, we have used GFP-labelled Enterobacteria phage T4 (GFP-T4-phage) as a model virus to study the viral scavenging function and metabolism in LSECs. The uptake of GFP-T4-phages was followed in real-time using deconvolution microscopy, and LSEC identity confirmed by visualization of fenestrae using structured illumination microscopy. By combining these imaging modalities with quantitative uptake and inhibition studies of radiolabelled GFP-T4-phages, we demonstrate that the bacteriophages are effectively degraded in the lysosomal compartment. Due to their high ability to take up and degrade circulating bacteriophages the LSECs may act as a primary anti-viral defence mechanism.

Dysregulated liver lipid metabolism and innate immunity associated with hepatic steatosis in neonatal BBdp rats and NOD mice

In a previous study we reported that prediabetic rats have a unique gene signature that was apparent even in neonates. Several of the changes we observed, including enhanced expression of pro-inflammatory genes and dysregulated UPR and metabolism genes were first observed in the liver followed by the pancreas. In the present study we investigated further early changes in hepatic innate immunity and metabolism in two models of type 1 diabetes (T1D), the BBdp rat and NOD mouse. There was a striking increase in lipid deposits in liver, particularly in neonatal BBdp rats, with a less striking but significant increase in neonatal NOD mice in association with dysregulated expression of lipid metabolism genes. This was associated with a decreased number of extramedullary hematopoietic clusters as well as CD68+ macrophages in the liver of both models. In addition, PPARɣ and phosphorylated AMPKα protein were decreased in neonatal BBdp rats. BBdp rats displayed decreased expression of antimicrobial genes in neonates and decreased M2 genes at 30 days. This suggests hepatic steatosis could be a common early feature in development of T1D that impacts metabolic homeostasis and tolerogenic phenotype in the prediabetic liver.

TLR3 Activation of Hepatic Stellate Cell Line Suppresses HBV Replication in HepG2 Cells.

There is limited information about the role of hepatic stellate cells (HSCs) in the liver innate immunity against hepatitis B virus (HBV) infection. We thus examined whether hepatic stellate cell line (LX-2) can be immunologically activated and produce antiviral factors that inhibit HBV replication in HepG2 cells. We found that LX-2 cells expressed the functional Toll-like receptor 3 (TLR3), activation of which by PolyI:C resulted in the selective induction of interferon-β (IFN-β) and IFN-λs, the phosphorylation of IFN regulatory factor 3 (IRF3) and IRF7. When HepG2 cells were treated with supernatant (SN) from PolyI:C-activated LX-2 cells, HBV replication was significantly inhibited. IFN-β and IFN-λ appeared to contribute to LX-2 SN-mediated HBV inhibition, as the antibodies to IFN-β and IFN-λ receptors could largely block the LX-2 SN action. Mechanistically, LX-2 SN treatment of the HepG2 cells induced a number of antiviral IFN-stimulated genes (ISGs: ISG20, ISG54, ISG56, OAS-1, Trim22, and Trim25) and facilitated the phosphorylation of STATs. These observations support further studies on the role of HSCs in the liver innate immunity against HBV infection.

Interplay between the Hepatitis B Virus and Innate Immunity: From an Understanding to the Development of Therapeutic Concepts.

The hepatitis B virus (HBV) infects hepatocytes, which are the main cell type composing a human liver. However, the liver is enriched with immune cells, particularly innate cells (e.g., myeloid cells, natural killer and natural killer T-cells (NK/NKT), dendritic cells (DCs)), in resting condition. Hence, the study of the interaction between HBV and innate immune cells is instrumental to: (1) better understand the conditions of establishment and maintenance of HBV infections in this secondary lymphoid organ; (2) define the role of these innate immune cells in treatment failure and pathogenesis; and (3) design novel immune-therapeutic concepts based on the activation/restoration of innate cell functions and/or innate effectors. This review will summarize and discuss the current knowledge we have on this interplay between HBV and liver innate immunity.

Characterization of liver changes in ZSF1 rats, an animal model of metabolic syndrome.

The non-alcoholic fatty liver disease is the hepatic counterpart of the metabolic syndrome. ZSF1 rats are a metabolic syndrome animal model in which liver changes have not been described yet. The characterization of liver histological and innate immunity changes in ZSF1 rats. Five groups of rats were included (n = 7 each group): healthy Wistar-Kyoto control rats (Ctrl), hypertensive ZSF1 lean (Ln), ZSF1 obese rats with a normal diet (Ob), ZSF1 obese rates with a high-fat diet (Ob-HFD), and ZSF1 obese rats with low-intensity exercise training (Ob-Ex). The animals were sacrificed at 20 weeks of age, their livers were collected for: a) measurements of the area of steatosis, fibrosis and inflammation (histomorphological analysis); and b) innate immunity (toll-like receptor [TLR] 2, TLR4, peroxisome proliferator-activated receptor γ [PPARγ], toll interacting protein [TOLLIP]) and inflammatory marker (tumor necrosis factor-alpha [TNFα], interleukin 1 [IL-1]) expression analysis by real-time PCR. Ob, Ob-HFD and Ob-Ex were significantly heavier than Ln and Ctrl animals. Ob, Ob-HFD and Ob-Ex animals had impaired glucose tolerance and insulin resistance. ZSF1 Ob, Ob-HFD and Ob-Ex presented a higher degree of steatosis (3,5x; p < 0.05) than Ctrl or ZSF1 Ln rats. Steatohepatitis and fibrosis were not observed in any of the groups. No differences in expression were observed between Ctrl, Ln and Ob animals (except for the significantly higher expression of TOLLIP observed in the Ob vs Ln comparison). Ob-HFD and Ob-Ex rats showed increased expression of PPARγ and TOLLIP as compared to other groups. However, both groups also showed increased expression of TLR2 and TLR4. Nevertheless, this did not translate into a differential expression of TNFα or IL-1 in any of the groups. The ZSF1 model is associated with liver steatosis but not with steatohepatitis or a significantly increased expression of innate immunity or inflammation markers.

Toll‐like receptor 3‐activated macrophages confer anti‐HCV activity to hepatocytes through exosomes

Exosomes are a class of cell-released small vesicles that mediate intercellular communication by delivering functional factors to recipient cells. During hepatitis C virus (HCV) infection, the interaction between liver resident macrophages and hepatocytes is a key component in liver innate immunity. In this study, we explored the role of exosomes in the delivery of innate anti-HCV factors to hepatocytes from macrophages. We showed that supernatant from TLR3-activated macrophage cultures could efficiently inhibit HCV replication in Huh7 cells. This macrophage-mediated anti-HCV activity was through exosomes because inhibiting exosomes could abrogate the action of macrophages. Further analyses demonstrated that TLR3-activated macrophages release exosomes that contain anti-HCV microRNA (miRNA)-29 family members. Inhibiting miRNA29 could restore HCV replication. These findings suggest a novel antiviral mechanism in liver innate immunity against HCV infection and provide insights to support further studies on developing exosome-based delivery system for disease treatment.-Zhou, Y., Wang, X., Sun, L., Zhou, L., Ma, T.-C., Song, L., Wu, J.-G., Li, J.-L., Ho, W.-Z. Toll-like receptor 3-activated macrophages confer anti-HCV activity to hepatocytes through exosomes.

HCV dsRNA-Activated Macrophages Inhibit HCV Replication in Hepatocytes.

Background:Macrophages play critical roles in innate immune response in the liver. Whether macrophages participate in liver innate immunity against HCV replication is poorly understoodObjectives:The aim of this study was to investigate the role of macrophages in liver innate immunity against HCV replication.Materials and Methods:Freshly isolated monocytes were purified from peripheral blood of healthy adult donors. Macrophages refer to 7-day-cultured monocytes in vitro. A hepatoma cell line (Huh7) was infected with HCV JFH-1 to generate in vitro HCV infectious system. RT-PCR was used to determine HCV RNA and mRNA levels of genes expression. ELISA was used to measure the protein level of interferon-α (IFN-α) and western blot was used to determine protein expression level of Toll-like receptor 3 (TLR3).Results:HCV dsRNA induced the expression of type I IFN (IFN-α/β) in monocyte-derived macrophages. HCV dsRNA also induced the expression of TLR3 and IFN regulatory factor-7 (IRF-7), the key regulators of the IFN signaling pathway. When HCV JFH-1-infected Huh7 cells were co-cultured with macrophages activated with HCV dsRNA or incubated in media conditioned with supernatant (SN) from HCV dsRNA-activated macrophages, HCV replication was significantly suppressed. This macrophage SN action on HCV inhibition was mediated through type I IFN, which was evidenced by the observation that antibody to type I IFN receptor could neutralize the macrophages-mediated anti-HCV effect. The role of type I IFN in macrophages-mediated anti-HCV activity is further supported by the observation that HCV dsRNA-activated macrophages SN treatment induced the expression of several IFN-stimulated genes (ISGs), ISG15, ISG56, OAS-1, OAS-2, MxA and Viperin in HCV-infected Huh7 cells.Conclusions:Macrophages may play an important role in liver innate immunity against HCV replication through a type I IFN-dependent mechanism.

Innate immunity induced by Plasmodium liver infection inhibits malaria reinfections.

Following transmission through a mosquito bite to the mammalian host, Plasmodium parasites first invade and replicate inside hepatocytes before infecting erythrocytes and causing malaria. The mechanisms limiting Plasmodium reinfections in humans living in regions of malaria endemicity have mainly been explored by studying the resistance induced by the blood stage of infection. However, epidemiologic studies have suggested that in high-transmission areas, preerythrocytic stages also activate host resistance to reinfection. This, along with the recent discovery that liver infections trigger a specific and effective type I interferon (IFN) response, prompted us to hypothesize that this pre-erythrocyte-stage-induced resistance is linked to liver innate immunity. Here, we combined experimental approaches and mathematical modeling to recapitulate field studies and understand the molecular basis behind such resistance. We present a newly established mouse reinfection model and demonstrate that rodent malaria liver-stage infection inhibits reinfection. This protection relies on the activation of innate immunity and involves the type I IFN response and the antimicrobial cytokine gamma IFN (IFN-γ). Importantly, mathematical simulations indicate that the predictions based on our experimental murine reinfection model fit available epidemiological data. Overall, our study revealed that liver-stage-induced innate immunity may contribute to the preerythrocytic resistance observed in humans in regions of malaria hyperendemicity.

Hepatic stellate cells, liver innate immunity, and hepatitis C virus

Chronic hepatitis C virus (HCV) infection can cause liver damage, ranging from mild to more severe conditions, such as fibrosis and cirrhosis. Hepatic stellate cell (HSC) activation is a key event in HCV-induced liver fibrosis. HSCs express several HCV coreceptors that interact with HCV proteins, promoting liver fibrogenesis. In addition, HSCs have the ability to engulf apoptotic bodies of hepatocytes induced by HCV and trigger a profibrogenic response. Recent studies have suggested that HSCs may play a novel role in the liver innate immunity. HSCs enhanced differentiation and accumulation of regulatory T cells. HSCs-activated natural killer cells could produce γ-interferon that inhibits HCV replication. Importantly, HSCs possess functional Toll-like receptor-3 and retinoic acid-inducible gene I that can be activated by their ligands (poly I :C, 5'ppp-dsRNA), leading to the induction of interferon and inhibition of HCV replication in hepatocytes. These new observations highlight the importance of HSCs in liver immunity against HCV, which is the focus of this review paper.

Induction of interferon‐λ contributes to Toll‐like receptor‐3‐activated hepatic stellate cell–mediated hepatitis C virus inhibition in hepatocytes

There is limited information about the role of hepatic stellate cells (HSC) in liver innate immunity against hepatitis C virus (HCV). We thus examined whether HSC can produce antiviral factors that inhibit HCV replication in human hepatocytes. HSC expressed functional Toll-like receptor 3 (TLR-3), which could be activated by its ligand, polyinosine-polycytidylic acid (poly I:C), leading to the induction of interferon-λ (IFN-λ) at both mRNA and protein levels. TLR-3 signalling of HSC also induced the expression of IFN regulatory factor 7 (IRF-7), a key regulator of IFN signalling pathway. When HCV JFH-1-infected Huh7 cells were co-cultured with HSC activated with poly I:C or incubated in media conditioned with supernatant (SN) from poly I:C-activated HSC, HCV replication was significantly suppressed. This HSC SN action on HCV inhibition was mediated through IFN-λ, which was evidenced by the observation that antibody to IFN-λ receptors could neutralize the HSC-mediated anti-HCV effect. The role of IFN-λ in HSC-mediated anti-HCV activity is further supported by the observation that HSC SN treatment induced the expression of IRF-7 and IFN-stimulated genes (ISGs), OAS-1 and MxA in HCV-infected Huh7 cells. These observations indicate that HSC may be a key regulatory bystander, participating in liver innate immunity against HCV infection using an IFN-λ-dependent mechanism.

Retinoic acid inducible gene-I (RIG-I) signaling of hepatic stellate cells inhibits hepatitis C virus replication in hepatocytes

Retinoic acid inducible gene-I (RIG-I) is critical in the activation of the type I IFN-dependent antiviral innate immune response to hepatitis C virus (HCV) infection. We examined whether hepatic stellate cells (HSC; LX-2) possess a functional RIG-I signaling pathway and produce antiviral factors that can inhibit HCV. We showed that LX-2 cells treated with the RIG-I ligand (5'ppp-dsRNA) expressed significantly higher levels of IFN-β and IFN-λ than the control cells. The RIG-I activation in LX-2 cells also induced the expression of Toll-like receptor 3 (TLR3) and IFN regulatory factor-7 (IRF-7), the key regulators of the IFN signaling pathway. When HCV Japanese fulminant hepatitis (JFH)-1-infected hepatocytes were co-cultured with LX-2 cells stimulated with 5'ppp-dsRNA or incubated in media conditioned with supernatant (SN) from 5'ppp-dsRNA-stimulated LX-2 cells, HCV replication in hepatocytes was suppressed significantly. This LX-2 cell action on HCV replication was mediated through both IFN-β and IFN-λ, as Abs to IFN-α/β or IFN-λ receptors could neutralize the LX-2 SN-mediated anti-HCV effect. The role of IFNs in LX-2 cell-mediated anti-HCV activity is further supported by the observation that LX-2 SN treatment induced the expression of IFN stimulated genes, 2'-5'-oligoadenylate synthase-1 (OAS-1) and myxovirus resistance A (MxA), in HCV-infected Huh7 cells. These observations highlight the importance of HSC in liver innate immunity against HCV infection via a RIG-I-mediated signaling pathway.

The role of innate immunity in HBV infection

Hepatitis B virus (HBV) infection is one of the main causes of chronic liver diseases. Whether HBV infection is cleared or persists is determined by both viral factors and host immune responses. It becomes clear that innate immunity is of importance in protecting the host from HBV infection and persistence. However, HBV develops strategies to suppress the antiviral immune responses. A combined therapeutic strategy with both viral suppression and enhancement of antiviral immune responses is needed for effective long-term clearance and cure for chronic HBV infection. We and others confirmed that bifunctional siRNAs with both gene silencing and innate immune activation properties are beneficial for inhibition of HBV and represent a potential approach for treatment of viral infection. Understanding the nature of liver innate immunity and their roles in chronic HBV progression and HBV clearance may aid in the design of novel therapeutic strategies for chronic HBV infection.

Antitumor Immunity Produced by the Liver Kupffer Cells, NK Cells, NKT Cells, and CD8+CD122+T Cells

Mouse and human livers contain innate immune leukocytes, NK cells, NKT cells, and macrophage-lineage Kupffer cells. Various bacterial components, including Toll-like receptor (TLR) ligands and an NKT cell ligand (α-galactocylceramide), activate liver Kupffer cells, which produce IL-1, IL-6, IL-12, and TNF. IL-12 activates hepatic NK cells and NKT cells to produce IFN-γ, which further activates hepatic T cells, in turn activating phagocytosis and cytokine production by Kupffer cells in a positive feedback loop. These immunological events are essentially evoked to protect the host from bacterial and viral infections; however, these events also contribute to antitumor and antimetastatic immunity in the liver by activated liver NK cells and NKT cells. Bystander CD8+CD122+ T cells, and tumor-specific memory CD8+T cells, are also induced in the liver by α-galactocylceramide. Furthermore, adoptive transfer experiments have revealed that activated liver lymphocytes may migrate to other organs to inhibit tumor growth, such as the lungs and kidneys. The immunological mechanism underlying the development of hepatocellular carcinoma in cirrhotic livers in hepatitis C patients and liver innate immunity as a double-edged sword (hepatocyte injury/regeneration, septic shock, autoimmune disease, etc.) are also discussed.