Mouse Model Of Acute Hepatitis Research Articles

The phthalide compound tokinolide B from Angelica sinensis exerts anti-inflammatory effects through Nur77 binding

BackgroundNur77, an orphan member of the nuclear receptor superfamily, regulates inflammatory diseases and is a therapeutic target for treating inflammation. Phthalides in Angelica sinensis exhibit anti-inflammatory activity. PurposeThis study aimed to screen compounds from A. sinensis phthalide extract that could exert anti-inflammatory activity by targeting Nur77. To provide new theoretical support for better elucidation of Chinese medicine targeting mitochondria to achieve multiple clinical efficacies. MethodsThe anti-inflammatory capacity of phthalides was assessed in tumor necrosis factor-alpha (TNF-α)-stimulated HepG2 cells using western blotting. The interaction between phthalides and Nur77 was verified by molecular docking, surface plasmon resonance, and cellular thermal shift assay. Co-immunoprecipitation, western blotting, and immunostaining were performed to determine the molecular mechanisms. The in vivo anti-inflammatory activity of the phthalides was evaluated in a lipopolysaccharide (LPS)/d-galactosamine (d-GalN)-induced acute hepatitis and liver injury mouse model of acute hepatitis and liver injury. Finally, the toxicity of phthalide toxicity was assessed in zebrafish experiments. ResultsAmong the 27 phthalide compounds isolated from A. sinensis, tokinolide B (TB) showed the best Nur77 binding capacity and, the best anti-inflammatory activity, which was induced without apoptosis. In vivo and in vitro experiments showed that TB promoted Nur77 translocation from the nucleus to the mitochondria and interacted with tumor necrosis factor receptor-associated factor 2 (TRAF2) and sequestosome 1 (p62) to induce mitophagy for anti-inflammatory functions. TB substantially inhibited LPS/d-GalN-induced acute hepatitis and liver injury in mice. TB also exhibited significantly lower toxicity than celastrol in zebrafish experiments. ConclusionThese findings suggested that TB inhibits inflammation by promoting Nur77 interaction with TRAF2 and p62, thereby inducing mitophagy. These findings offer promising directions for developing novel anti-inflammatory agents, enhance the understanding of phthalide compounds, and highlight the therapeutic potential of traditional Chinese herbs.

Comparative analysis of isothiocyanates in eight cruciferous vegetables and evaluation of the hepatoprotective effects of 4-(methylsulfinyl)-3-butenyl isothiocyanate (sulforaphene) from daikon radish (Raphanus sativus L.) sprouts.

The contributions of cruciferous vegetables to human health are widely recognised, particularly at the molecular level, where their isothiocyanates play a significant role. However, compared to the well-studied isothiocyanate 4-(methylsulfinyl)butyl isothiocyanate (sulforaphane) produced from broccoli sprouts, less is known about the pharmacological effects of other isothiocyanates and the stage of vegetables preferable to obtain their benefits. We analysed the quantity and quality of isothiocyanates produced in both the sprouts and mature stages of eight cruciferous vegetables using gas chromatography-mass spectrometry (GC-MS). Additionally, we investigated the hepatoprotective effects of isothiocyanates in a mouse model of acute hepatitis induced by carbon tetrachloride (CCl4). Furthermore, we explored the detoxification enzyme-inducing activities of crude sprout extracts in normal rats. Among the eight cruciferous vegetables, daikon radish (Raphanus sativus L.) sprouts produced the highest amount of isothiocyanates, with 4-(methylsulfinyl)-3-butenyl isothiocyanate (sulforaphene) being the dominant compound. The amount of sulforaphene in daikon radish sprouts was approximately 30 times that of sulforaphane in broccoli sprouts. Sulforaphene demonstrated hepatoprotective effects similar to sulforaphane in ameliorating CCl4-induced hepatic injury in mice. A crude extract of 3-day-old daikon radish sprouts upregulated the detoxifying enzyme glutathione S-transferase (GST) in the liver, whereas the crude extract of broccoli sprouts showed limited upregulation. This study highlights that daikon radish sprouts and sulforaphene have the potential to serve as functional food materials with hepatoprotective effects. Furthermore, daikon radish sprouts may exhibit more potent hepatoprotective effects compared to broccoli sprouts.

TPN10475 alleviates concanavalin A-induced autoimmune hepatitis by limiting T cell development and function through inhibition of PI3K-AKT pathway

Autoimmune hepatitis (AIH) is an inflammatory liver disease in which the autoimmune system instigates an attack on the liver, causing inflammation and liver injury, and its incidence has increased worldwide in recent years. The mouse model of acute hepatitis established by concanavalin A (Con A) is a typical and recognized mouse model for the study of T-cell-dependent liver injury. In this study, we aimed to investigate whether the artemisinin derivative TPN10475 could alleviate AIH and its possible mechanisms. TPN10475 effectively inhibited lymphocyte proliferation and IFN-γ+ T cells production in vitro, alleviated liver injury by decreasing infiltrating inflammatory T cells producing IFN-γ in the liver and peripheral immune tissues, and demonstrated that TPN10475 weakened the activation and function of T cells by inhibiting PI3K-AKT signaling pathway. These results suggested that TPN10475 may be a potential drug for the treatment of AIH, and the inhibition of PI3K-AKT signaling pathway may provide new ideas for the study of the pathogenesis of AIH.

FRI-348 - The cell cycle protein Cyclin E1 mediates pro-inflammatory signals in a mouse model of acute hepatitis and in primary macrophages

FRI-348 - The cell cycle protein Cyclin E1 mediates pro-inflammatory signals in a mouse model of acute hepatitis and in primary macrophages

The Protective Role of IL-36/IL-36R Signal in Con A-Induced Acute Hepatitis

Abstract The IL-36 family, including IL-36α, IL-36β, IL-36γ, and IL-36 receptor antagonist (IL-36Ra), belongs to the IL-1 super-family. Although IL-36 is known to play a role in autoimmune diseases, it remains unclear as how IL-36 regulates inflammation in the liver. To determine the role of IL-36/IL-36R signaling pathways, we established an acute hepatitis mouse model by intravenous injection of the plant lectin concanavalin A (Con A), and found that the levels of IL-36 were increased in the liver following Con A injection. We also demonstrated that intrahepatic leukocytes, but not hepatocytes, were the main source of IL-36. Moreover, further research verified that infiltrated neutrophils were the main source of IL-36γ in the liver. Using the IL-36R knockout mouse model (H-2b), surprisingly, we found that the absence of IL-36 signals led to aggravated liver injuries, as evidenced by increased mortality, accompanied by elevated serum ALT and AST levels and severe pathological changes in the liver. Further investigations demonstrated that a lack of IL-36 signaling induced intrahepatic activation of CD4+ and CD8+T lymphocytes and increased the production of inflammatory cytokines. In addition, IL-36R knockout mice had reduced Treg cell functions and chemotaxis in the liver. Together, our results suggest a vital role of IL-36 in regulating T cell function and homeostasis during liver injury and inflammation. Supported by grants from NIH (R01 EY028773, AI132674, R21 AI153586)

The Protective Role of IL-36/IL-36R Signal in Con A-Induced Acute Hepatitis.

The IL-36 family, including IL-36α, IL-36β, IL-36γ, and IL-36R antagonist, belong to the IL-1 superfamily. It was reported that IL-36 plays a role in immune diseases. However, it remains unclear how IL-36 regulates inflammation. To determine the role of IL-36/IL-36R signaling pathways, we established an acute hepatitis mouse model (C57BL/6) by i.v. injection of the plant lectin Con A. We found that the levels of IL-36 were increased in the liver after Con A injection. Our results demonstrated the infiltrated neutrophils, but not the hepatocytes, were the main source of IL-36 in the liver. Using the IL-36R-/- mouse model (H-2b), we surprisingly found that the absence of IL-36 signals led to aggravated liver injury, as evidenced by increased mortality, elevated serum alanine aminotransferase and aspartate aminotransferase levels, and severe liver pathological changes. Further investigations demonstrated that a lack of IL-36 signaling induced intrahepatic activation of CD4+ and CD8+ T lymphocytes and increased the production of inflammatory cytokines. In addition, IL-36R-/- mice had reduced T regulatory cell numbers and chemokines in the liver. Together, our results from the mouse model suggested a vital role of IL-36 in regulating T cell function and homeostasis during liver inflammation.

Lysimachiae Herba Inhibits Inflammatory Reactions and Improves Lipopolysaccharide/D-Galactosamine-Induced Hepatic Injury.

This study aimed to determine the anti-inflammatory and hepatoprotective effects of Lysimachiae Herba ethanolic extract (LHE) in lipopolysaccharide (LPS)-stimulated macrophages and in a LPS/D-galactosamine (GalN)-induced acute hepatitis mouse model. Then, the production of inflammatory mediators and the activation of related pathways in macrophages were explored. Finally, we assessed the serum aminotransferase levels and the expression of inflammatory/antioxidant molecules in liver tissues in mice. Results revealed that LHE treatment significantly inhibited the production of inflammatory mediators in LPS-stimulated RAW 264.7 macrophages. Molecular data showed that LHE remarkably increased the activities of the antioxidant pathway and inhibited the phosphorylation of mitogen-activated protein kinase as well as the transcriptional activity of nuclear factor-κB induced by LPS. Furthermore, it prevented acute liver damage caused by LPS/D-GalN-induced hepatitis by inhibiting aminotransferase levels and histopathological changes in mice. Moreover, treatment with LHE significantly inhibited the activation of inflammatory pathways and increased the expression of antioxidant molecules including heme oxygenase-1/Nuclear factor erythroid 2-related factor 2. In conclusion, LHE has potent anti-inflammatory and hepatoprotective effects in LPS-stimulated macrophages and the LPS/D-GalN-induced acute hepatitis mouse model. Thus, it can be a treatment option for inflammation, hepatitis, and liver injury.

Antioxidant and Anti-Inflammatory Effects of Bischofia javanica (Blume) Leaf Methanol Extracts through the Regulation of Nrf2 and TAK1.

Bischofia javanica (Blume) has been traditionally used to treat inflammatory diseases such as tonsillitis and ulcers throughout Asia, including China, Indonesia, and the Philippines: however, the molecular mechanisms by which B. javanica exerts its antioxidant and anti-inflammatory properties remain largely unknown. In this study, we analyzed the antioxidant and anti-inflammatory mechanisms of methanol extracts of B. javanica leaves (MBJ) in vitro and in vivo. MBJ decreased nitric oxide (NO) production and the expression of pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, in lipopolysaccharide (LPS)-treated RAW 264.7 cells. The observed suppression of inflammatory responses by MBJ was correlated with an inhibition of the nuclear factor-κB (NF-κB) and the mitogen-activated protein kinase (MAPK) pathways. Additionally, MBJ induced nuclear translocation of the nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that upregulates the expression of anti-inflammatory and antioxidant genes. Furthermore, MBJ exhibited antioxidant and anti-inflammatory effects in an acute hepatitis mouse model. In conclusion, our results confirm the medicinal properties of B. javanica, and therefore MBJ could be applied to improve inflammatory and redox imbalances in different types of pathologies.

Loss of CCR5 signaling results in early NK cell and neutrophil recruitment into the liver and increased hepatic inflammation in a mouse model of acute hepatitis B

Abstract Human genetic studies demonstrate that a non-functional CCR5 receptor sequence variant is associated with enhanced control of acute hepatitis B virus (HBV) infection. To better understand the role of CCR5 in immune responses to HBV, we employed a mouse model of acute HBV in which Ccr5 +/+(WT) or Ccr5 −/−(KO) C57BL/6 mice were intravenously infected with adenovirus containing an overlapping HBV1.3 construct (AdHBV) or vector control (AdShuttle). Mice (N=4–6/group) were euthanized at days 2, 3, 7, 10, and 14 post injection. Increased plasma ALT levels were observed in both Ccr5 WT and KO AdHBV mice at day 7, but levels were significantly higher in the Ccr5 KO compared to WT mice by day 14 (554 vs 274 U/L, p < 0.05). Plasma ALT levels were not significantly different between Ccr5 WT and KO AdShuttle mice. Analysis of intrahepatic leukocytes by flow cytometry revealed significantly increased intrahepatic CD11b+ NK cells (26.3 vs 6.9, % of live leukocytes, p< 0.01) and neutrophils (7.3 vs 1.3, % of live leukocytes, p< 0.05) at day 3 in Ccr5 KO compared to WT AdHBV mice. By day 7, these differences in cell populations were no longer present. At Day 14, significantly higher levels of intrahepatic Ly6c+ macrophages were detected in Ccr5 KO compared to WT AdHBV mice (17.0 vs 6.4, % of live leukocytes, p< 0.01). These differences in intrahepatic leukocytes were not observed in AdShuttle mice. Loss of Ccr5 function did not significantly alter intrahepatic CD4+ and CD8+ populations at the time points investigated. Taken together, these findings suggest that loss of Ccr5 signaling increases intrahepatic innate cells and inflammation during acute HBV infection, providing evidence for a role of CCR5 in regulation of innate immune responses to acute HBV infection.

Activation of intrahepatic CD4+CXCR5+ T and CD19+ B cells is associated with viral clearance in a mouse model of acute hepatitis B virus infection.

The role of immunity in the pathogenesis of acute hepatitis B virus (HBV) infection is poorly understood. The purpose of this research was to define the intrahepatic immune factors responsible for viral clearance during acute HBV infection. The model of acute HBV infection was established by hydrodynamically transfecting mice with pCDNA3.1-HBV1.3 plasmids which contained a supergenomic HBV1.3-length transgene. The frequency of CD4+ CXCR5+ T cells, CD19+ B cells and their surface molecules in livers, spleens and peripheral blood were detected using flow cytometry. The lymphomononuclear cells isolated from the livers of transfected mice were further stimulated by HBc-derived peptides and then the frequency and cytokine secretion of HBV-specific CD4+CXCR5+ T cells were detected. We found that the frequency of CXCR5+ in CD4+ T cells was specifically increased; the expression of PD-1 was decreased while the expression of ICOS was increased on intrahepatic CD4+CXCR5+ T cells. Although the frequency of CD19+ B cells was not affected, the expression of PDL-1, ICOSL and IL-21R on B cells was increased in the livers of mice. The frequency of HBV-specific CD4+CXCR5+ T cells and the production of IL-21 by intrahepatic CD4+CXCR5+ T cells of mice with acute HBV infection were increased after stimulation. Furthermore, the expression of function-related molecules of intrahepatic CD4+CXCR5+ T, including Bcl-6, CXCR5, IL-6, IL-6R, IL-21 and IL-4 in the liver was increased during acute HBV infection. In conclusion, the activation of intrahepatic CD4+CXCR5+ T cells and B cells was associated with the clearance of HBV during acute infection.

MAPK/AP-1-Targeted Anti-Inflammatory Activities of Xanthium strumarium.

Xanthium strumarium L. (Asteraceae), a traditional Chinese medicine, is prescribed to treat arthritis, bronchitis, and rhinitis. Although the plant has been used for many years, the mechanism by which it ameliorates various inflammatory diseases is not yet fully understood. To explore the anti-inflammatory mechanism of methanol extracts of X. strumarium (Xs-ME) and its therapeutic potential, we used lipopolysaccharide (LPS)-stimulated murine macrophage-like RAW264.7 cells and human monocyte-like U937 cells as well as a LPS/D-galactosamine (GalN)-induced acute hepatitis mouse model. To find the target inflammatory pathway, we used holistic immunoblotting analysis, reporter gene assays, and mRNA analysis. Xs-ME significantly suppressed the up-regulation of both the activator protein (AP)-1-mediated luciferase activity and the production of LPS-induced proinflammatory cytokines, including interleukin (IL)-1[Formula: see text], IL-6, and tumor necrosis factor (TNF)-[Formula: see text]. Moreover, Xs-ME strongly inhibited the phosphorylation of mitogen-activated protein kinase (MAPK) in LPS-stimulated RAW264.7 and U937 cells. Additionally, these results highlighted the hepatoprotective and curative effects of Xs-ME in a mouse model of LPS/D-GalN-induced acute liver injury, as assessed by elevated serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and histological damage. Therefore, our results strongly suggest that the ethnopharmacological roles of Xs-ME in hepatitis and other inflammatory diseases might result from its inhibitory activities on the inflammatory signaling of MAPK and AP-1.

Kupffer-cell-expressed transmembrane TNF-α is a major contributor to lipopolysaccharide and D-galactosamine-induced liver injury

Tumor necrosis factor (TNF)-α exists in two bioactive forms, a 26-kDa transmembrane form (tmTNF-α) and a 17-kDa soluble form (sTNF-α). sTNF-α has been recognized as a key regulator of hepatitis; however, serum sTNF-α disappears in mice during the development of severe liver injury, and high levels of serum sTNF-α do not necessarily result in liver damage. Interestingly, in a mouse model of acute hepatitis, we have found that tmTNF-α expression on Kupffer cells (KCs) significantly increases when mice develop severe liver injury caused by lipopolysaccharide (LPS)/D-galactosamine (D-gal), and the level of tmTNF-α expression is positively related to the activity of serum transaminases. Therefore, we hypothesized that KC-expressed tmTNF-α constitutes a pathomechanism in hepatitis and have explored the role of tmTNF-α in this disease model. Here, we have compared the impact of KCs(tmTNFlow) and KCs(tmTNFhigh) on acute hepatitis in vivo and ex vivo and have further demonstrated that KCs(tmTNFhigh), rather than KCs(tmTNFlow), not only exhibit an imbalance in secretion of pro- and anti-inflammatory cytokines, favoring inflammatory response and exacerbating liver injury, but also induce hepatocellular apoptosis via tmTNF-α and the expression of another pro-apoptotic factor, Fas ligand. Our data suggest that KC(tmTNFhigh) is a major contributor to liver injury in LPS/D-gal-induced hepatitis.

P0461 : Increased liver gamma delta T cells accompanied by enhanced innate immune responses in mouse model of acute hepatitis B virus (HBV) infection by hydrodynamics-based in vivo transfection of HBV-DNA

P0461 : Increased liver gamma delta T cells accompanied by enhanced innate immune responses in mouse model of acute hepatitis B virus (HBV) infection by hydrodynamics-based in vivo transfection of HBV-DNA

AP-1-Targeting Anti-Inflammatory Activity of the Methanolic Extract of Persicaria chinensis.

In traditional Chinese medicine, Persicaria chinensis L. has been prescribed to cure numerous inflammatory disorders. We previously analyzed the bioactivity of the methanol extract of this plant (Pc-ME) against LPS-induced NO and PGE2 in RAW264.7 macrophages and found that it prevented HCl/EtOH-induced gastric ulcers in mice. The purpose of the current study was to explore the molecular mechanism by which Pc-ME inhibits activator protein- (AP-) 1 activation pathway and mediates its hepatoprotective activity. To investigate the putative therapeutic properties of Pc-ME against AP-1-mediated inflammation and hepatotoxicity, lipopolysaccharide- (LPS-) stimulated RAW264.7 and U937 cells, a monocyte-like human cell line, and an LPS/D-galactosamine- (D-GalN-) induced acute hepatitis mouse model were employed. The expression of LPS-induced proinflammatory cytokines including interleukin- (IL-) 1β, IL-6, and tumor necrosis factor-α (TNF-α) was significantly diminished by Pc-ME. Moreover, Pc-ME reduced AP-1 activation and mitogen-activated protein kinase (MAPK) phosphorylation in both LPS-stimulated RAW264.7 cells and differentiated U937 cells. Additionally, we highlighted the hepatoprotective and curative effects of Pc-ME pretreated orally in a mouse model of LPS/D-GalN-intoxicated acute liver injury by demonstrating the significant reduction in elevated serum AST and ALT levels and histological damage. Therefore, these results strongly suggest that Pc-ME could function as an antihepatitis remedy suppressing MAPK/AP-1-mediated inflammatory events.

AP-1-Targeted Inhibition of Macrophage Function and Lipopolysaccharide/D-Galactosamine-Induced Hepatitis by Phyllanthus acidus Methanolic Extract.

Traditionally, Phyllanthus acidus (Phyllanthaceae) has been used for the treatment of rheumatism, bronchitis, asthma, respiratory disorders, and hepatitis. Recently, we showed that a methanol extract of Phyllanthaceae (Pa-ME) has a potent anti-inflammatory activity in RAW264.7 cells and strongly ameliorates HCl / EtOH -induced gastric ulcers in mice by targeting the Src/Syk of NF-κB. In the present study, we explored the molecular mechanism of Pa-ME on the AP-1 activation pathway and evaluated its potential hepatoprotective effects. To do this, we employed lipopolysaccharide (LPS)-stimulated RAW264.7 cells and U937 cells and an LPS/D-galactosamine (D- GaIN )-induced acute hepatitis mouse model. We utilized a multitude of assays, including immunoblotting analysis, reporter gene assays, and mRNA expression analysis, to determine the effect of Pa-ME on the AP-1 pathway. Pa-ME strikingly suppressed the production of LPS-induced pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). Furthermore, Pa-ME also strongly inhibited activator protein-1 (AP-1) activation and mitogen-activated protein kinase (MAPK) phosphorylation in LPS-stimulated RAW264.7 macrophages cells and the U937 monocyte like human cell line. Moreover, pre-treatment with Pa-ME exhibited strong hepatoprotective and curative effects in an LPS/D-Gal-induced mouse hepatitis model as evidenced by a decrease in elevated serum AST and ALT levels and the amelioration of histological damage. Taken together, our data suggest that Pa-ME might play a crucial ethnopharmacological role as a hepatoprotective herbal remedy by suppressing MAPK signaling and the activity of the downstream transcription factor AP-1.

The in vivo evaluation of the therapeutic potential of human adipose tissue-derived mesenchymal stem cells for acute liver disease.

Mesenchymal stem cells (MSCs) have emerged as an attractive candidate for cell therapy applications. In the prior decade, many animal studies have demonstrated that MSCs are therapeutically beneficial for the treatment of liver disease. The carbon tetrachloride (CCl4)-induced acute hepatitis model has been the most widely used model in these studies. Our group has utilized the CCl4-induced mouse hepatitis model to study the therapeutic potential of human adipose tissue-derived MSCs (hADSCs). We have demonstrated that systemically administered hADSCs engrafted into the damaged liver and promoted tissue repair. This phenomenon likely reflected the paracrine effects of the administered hADSCs. In this chapter, we describe a method to evaluate the therapeutic efficacy of the systemic administration of hADSCs in the CCl4-induced mouse model of acute hepatitis.

The magnitude of acute hepatitis is more limited by regulation of cytokine signalling than apoptosis of liver-infiltrating effector CD8 T cells (P4174)

Abstract Acute hepatitis is often mediated by CD8 T cells that kill target cells or secrete hepatotoxic cytokines. However, the parameters regulating CD8 T cell-mediated acute hepatitis are not well understood. We used the well-characterized Met-Kb Tg mouse model of acute hepatitis, in which hepatitis is mediated by lymph node activated TCR Tg CD8 recognizing their cognate antigen in the liver. To investigate whether cytokine regulation or apoptosis of CD8 T cells were critical in limiting acute hepatocellular injury, adoptive transfer experiments were performed using TCR Tg T cells deficient for either suppressor of cytokine signaling (SOCS-1) or the pro-apoptotic molecule Bim. Although there was a substantial accumulation of Bim-/- Tg cells, the outcome of hepatitis remained unchanged, suggesting that effector T cell survival was not a critical parameter in limiting liver damage. In contrast, SOCS-1-/- Tg T cells induced a heightened severity of hepatitis than their wt counterparts. SOCS-1-/- Tg cells isolated from the liver displayed upregulated IL-2Rα, required for the high affinity IL-2 receptor, and was associated with higher levels of IFN-γ expression, CTL activity, and proliferation rates, consistent with enhanced effector function. These data support a critical role for cytokines in CTL function, and demonstrate that the propensity of CD8 T cells to mediate acute hepatitis is determined by the quality rather than the number of CTLs infiltrating the liver.

Hepatic T cell suppressors and their inhibition roles in hepatic viral clearance (P6353)

Abstract The unique microenvironment of the liver favors T cell inactivation, tolerance, and apoptosis. As such, it is a challenging environment in which to efficiently clear viruses, which may explain why HBV and HCV often establish a chronic viral presence. The principal mechanisms that account for hepatic T cell failure and thus influence the outcome of liver infections, including the identification of inhibitory molecules and their ligands, are beginning to be understood. We recently identified LSECtin from the liver and reported that LSECtin negatively regulates T cell receptor-mediated signaling and T cell Immunity. We then investigate whether LSECtin regulates anti-viral immunity and virus invasiveness in the liver. Using a mouse model infected with a hepatotropic adenovirus, we found that the absence of LSECtin led to a higher frequency of CTL, which produced higher levels of antiviral cytokines and cytotoxic factors and showed increased expression of T-bet and Runx3, thus mediated more efficient virus-specific cytotoxity than WT cells. As a consequence, LSECtin deficiency significantly accelerated liver adenovirus clearance. We further constructed an immunocompetent mouse model of acute hepatitis B viral infection to demonstrate that LSECtin significantly delayed clearance of HBV from blood and infected hepatocytes through limiting the frequency of HBV-specific IFN-γ-producing cells.

Liver Sinusoidal Endothelial Cell Lectin Inhibits CTL-Dependent Virus Clearance in Mouse Models of Viral Hepatitis

Liver sinusoidal endothelial cell lectin (LSECtin) was recently reported to suppress intrahepatic T cell immunity and to limit immune-mediated liver injury. However, its role in the outcome and pathogenesis of viral infection has not yet been elucidated. Using a mouse model infected with a hepatotropic adenovirus, we found that the absence of LSECtin led to a higher frequency of intrahepatic effector CTLs. These cells produced higher levels of antiviral cytokines and cytotoxic factors and exhibited an increased expression of the transcription factors T-bet and Runx3. This phenotype observed in the LSECtin-knockout cells mediated a more efficient virus-specific cytotoxicity compared with that of wild-type cells. As a consequence, LSECtin deficiency significantly accelerated liver adenovirus clearance. In contrast, LSECtin upregulation in the liver delayed viral clearance; this delayed clearance was accompanied by the downregulation of the antiviral activity of CTLs. We further constructed an immunocompetent mouse model of acute hepatitis B viral infection to demonstrate that LSECtin significantly delayed the clearance of hepatitis B virus from blood and infected hepatocytes by limiting the frequency of hepatitis B virus-specific IFN-γ-producing cells. Consistent with this function, LSECtin was upregulated in the liver of mouse models of viral hepatitis. Taken together, our results suggest that LSECtin may facilitate the reduction of liver inflammation at the cost of delaying virus clearance and that this effect might be hijacked by the virus as an escape mechanism.

P.042 Studies on the control of HBV infection in a mouse model of acute hepatitis B

P.042 Studies on the control of HBV infection in a mouse model of acute hepatitis B