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Abstract

  1. Top of page
  2. Abstract
  3. TLRs, Adaptor Molecules, and Signaling
  4. Negative Regulation in TLR Signaling
  5. Intracellular Recognition Receptors
  6. TLR Expression in the Liver
  7. TLR Signaling in Liver Disease
  8. TLRs and Infectious Liver Diseases
  9. Alcohol-Induced Liver Diseases
  10. NASH
  11. Hepatic Fibrosis
  12. HCV Infection
  13. HBV Infection
  14. Ischemia/Reperfusion Liver Injury
  15. Liver Regeneration
  16. HCC
  17. Hepatic Immune Disorders
  18. Perspectives
  19. Acknowledgements
  20. References

Toll-like receptors (TLRs) are pattern recognition receptors that recognize pathogen-associated molecular patterns and signal through adaptor molecules, myeloid differentiation factor 88 (MyD88), Toll/IL-1 receptor domain containing adaptor protein (TIRAP), Toll/IL-1 receptor domain containing adaptor inducing interferon-β (TRIF), and TRIF-related adaptor molecule (TRAM) to activate transcription factors, nuclear factor (NF)-κB, activator protein 1 (AP-1), and interferon regulatory factors (IRFs) leading to the initiation of innate immunity. This system promptly initiates host defenses against invading microorganisms. Endogenous TLR ligands such as the products from dying cells may also engage with TLRs as damage-associated molecular patterns. Although Kupffer cells are considered the primary cells to respond to pathogen associated molecular patterns in the liver, recent studies provide evidence of TLR signaling in hepatic nonimmune cell populations, including hepatocytes, biliary epithelial cells, endothelial cells, and hepatic stellate cells. This review highlights advances in TLR signaling in the liver, the role of TLRs in the individual hepatic cell populations, and the implication of TLR signaling in acute and chronic liver diseases. We further discuss recent advances regarding cytosolic pattern recognition receptors, RNA helicases that represents a new concept in chronic hepatitis C virus infection. (HEPATOLOGY 2008.)

Toll-like receptors (TLRs) facilitate innate immune responses for the initial host defense against microorganisms. TLRs are widely expressed on immune cells and recognize distinct microorganism products as pathogen-associated molecular patterns (PAMPs).1 Some TLRs are located on the endosome-lysosome membrane. Upon the recognition of PAMPs, TLR signaling promptly induces potent innate immune responses that signal through adaptor molecules myeloid differentiation factor 88 (MyD88), Toll/interleukin (IL)-1 receptor (TIR) domain containing adaptor protein (TIRAP), TIR-domain containing adaptor inducing interferon (IFN)-β (TRIF), and TRIF-related adaptor molecule (TRAM) to activate transcription factors, nuclear factor (NF)-κB, activator protein 1 (AP-1), and interferon regulatory factors (IRFs) to induce antibacterial and antiviral responses.1–3 The liver is constantly exposed to microbial products from the enteric microflora that are carried through the portal circulation to the liver.4–6 However, no obvious inflammation occurs in the healthy liver. The liver normally regulates innate immune responses partly through the modulation of TLR signals, namely “liver tolerance.”4, 5, 7, 8 A breakdown of tolerance may induce an inappropriate immune response, resulting in acute and chronic inflammatory liver diseases. Not only PAMPs derived from microbes, but also endogenous components derived from dying host cells, termed damage-associated molecular patterns (DAMPs), ligate to and activate TLRs.9 In addition to TLRs, microbial components that enter the cell's cytoplasm are also detected by cytosolic pattern recognition receptors, such as nucleotide-binding oligomerization domain (NOD)-like receptors and the RNA-helicase family. In the liver, TLR-mediated signals are associated with infectious, granulomatous, and alcoholic liver disease, ischemia-reperfusion injury, and liver regeneration. Recent studies also provide evidence for a role of TLRs in the pathophysiology of nonalcoholic steatohepatitis (NASH), autoimmune hepatitis, primary biliary cirrhosis (PBC), hepatic fibrosis, and hepatocarcinogenesis, and in the function of RNA-helicases, particularly in chronic hepatitis C virus (HCV) infection.

TLRs, Adaptor Molecules, and Signaling

  1. Top of page
  2. Abstract
  3. TLRs, Adaptor Molecules, and Signaling
  4. Negative Regulation in TLR Signaling
  5. Intracellular Recognition Receptors
  6. TLR Expression in the Liver
  7. TLR Signaling in Liver Disease
  8. TLRs and Infectious Liver Diseases
  9. Alcohol-Induced Liver Diseases
  10. NASH
  11. Hepatic Fibrosis
  12. HCV Infection
  13. HBV Infection
  14. Ischemia/Reperfusion Liver Injury
  15. Liver Regeneration
  16. HCC
  17. Hepatic Immune Disorders
  18. Perspectives
  19. Acknowledgements
  20. References

TLRs were originally identified as homologs of Drosophila Toll that regulate dorso-ventral embryonic polarity and are essential for antifungal immunity. A total of 13 mammalian TLR members containing a conserved TIR domain in their intracellular domain and an individual leucine rich repeat domain in their extracellular domain have been identified. TLR1, TLR2, TLR4, TLR5, and TLR6 are expressed on the cell surface and TLR3, TLR7, TLR8, and TLR9 are expressed on the endosome-lysosome membrane (Fig. 1).1 TLR1 and TLR2 heterodimerize and recognize bacterial triacylated lipopeptides.1 Heterodimers of TLR2 with TLR6 recognize bacterial diacylated lipopeptides.1 TLR4 and TLR5 are the receptors for the Gram-negative bacterial cell wall components, lipopolysaccharide (LPS), and bacterial flagellin, respectively.1 Intracellular TLRs, TLR3, TLR7/8, and TLR9 detect viral-derived and synthetic double-stranded RNA, viral-related single-stranded RNA, and bacterial unmethylated CpG-DNA, respectively.10–13 The ligands for TLR10, TLR12, and TLR13 remain unidentified. TLR8 does not signal in mice. TLR10 is expressed in humans but not in mice. TLR11, TLR12, and TLR13 are expressed in mice but not in humans. TLRs also sense endogenous ligands initiating danger signals. TLR4 detects endogenous ligands, such as high mobility group box 1 (HMGB1), hyaluronan, heat shock protein 60, and free fatty acids (C12:0, C14:0, C16:0, and C18:0).14–16 Recent reports demonstrated that necrotic cells stimulate TLR2 and TLR4 associated with MyD88 under sterile conditions.9, 17

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Figure 1. Schematic overview of TLR signaling pathways. TLR4, TLR5, TLR1/2, and TLR2/6 are located on cell surface and recognize LPS, flagellin, triacyl lipopeptides, and diacyl lipopeptides, respectively. TLR3, TLR7/8, and TLR9 expressed on endosome membrane and sense double-stranded RNA, single-stranded RNA, and CpG-DNA, respectively. All TLRs expect for TLR3 signal-transmit through MyD88 to the activation of NF-κB and p38/c-Jun N-terminal kinase (JNK). TIRAP bridges TLR2 and TLR4 with MyD88. TRAF is utilized by TLR3 and TLR4/TRAM to activate TBK1/inhibitor of NF-κB kinase (IKK)ϵ leading to IRF-3 activation followed by IFN-β production. TLR7/8 and TLR9 induce IFN-α through MyD88/IRAK1/IRF7/IKKα.

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All members of TLR, except for TLR3, associate with a common adaptor molecule, MyD88, through interaction of their intracellular TIR domains to trigger inflammatory responses.18, 19 TLR3 and TLR4 utilize another adaptor protein, TRIF, to induce type I IFN.20 TLR4 requires the association with LPS-binding protein (LBP), CD14, and MD2 to recognize LPS.1 Upon TLR4 ligation, the intracellular domain of TLR4 recruits TIRAP and MyD88 for MyD88-dependent signaling and TRAM bridges TRIF for MyD88-independent signaling.21, 22

MyD88 was characterized as a key component in the IL-1 and IL-18 signaling cascades.18 Subsequently, MyD88-deficient mice also were shown to be unresponsive to ligands for TLR2, TLR4, TLR5, TLR7, and TLR9. TLR2 and TLR4 utilize TIRAP to transmit to the MyD88-dependent pathway.1, 3 The MyD88-dependent pathway activates p38, c-Jun N-terminal kinase (JNK) and inhibitor of NF-κB kinase (IKK) kinase/NF-κB through a signaling cascade that involves the sequential recruitment of IL-1R-associated kinase (IRAK) 4, IRAK1 associating with tumor necrosis receptor-associated factor (TRAF) 6, transforming growth factor-β-activated kinase 1 (TAK1), and TAK1-binding protein 2 (TAB2).1 Additionally, ubiquitinating factors ubiquitin-conjugating enzyme E2 variant 1 (UEV1A) and ubiquitin-conjugating enzyme 13 (UBC13) modulate the activation of TRAF6 and TAK1.1, 23 MyD88 also functions in IFNγ receptor 1 (IFNγR1) signaling. IFNγR1 recruits mixed-lineage kinase 3 (MLK3) through MyD88, which in turn activates p38.24 IRFs are the key in TLR signaling. IRF5, which interacts with MyD88 in all stimulated TLRs, is required for proinflammatory cytokine production, such as tumor necrosis factor (TNF)-α, IL-12, and IL-6.25 IRF7 interacts with MyD88, IRAK1, and IKK α, which are activated by TLR7 or TLR9, to induce IFN-α production.1, 26–28 In addition, TLR2-mediated MyD88-dependent signaling recruits Fas-associated death domain (FADD) leading to caspase-8 activation and subsequent caspase-3-mediated apoptosis.29

The MyD88-independent TRIF-dependent pathway is activated by TLR3 and TLR4/TRAM. TRIF associates with TRAF family member associated NF-κB activator binding kinase 1 (TBK1) and IKKϵ with subsequent phosphorylation and nuclear translocation of IRF3 leading to IFN-β transcription.1 Upon the activation of TLR3 or TLR4, TRIF also associates with RIP1 to activate NF-κB and simultaneously to recruit FADD resulting in apoptosis through activation of caspase-8.30–32 Alternatively, TRAF3 has a key role in both MyD88-dependent and TRIF-dependent signaling, which is involved in the induction of type I IFN and IL-10, but not proinflammatory cytokines, in response to TLR3, TLR4 and TLR9 stimulation.33

The MyD88-independent TRIF-dependent pathway induces dendritic cell-maturation with the upregulation of MHC class II and costimulatory molecules (CD80 and CD86) by the stimulation of TLR4 and TLR3.1, 10, 20

The TLR4-mediated MyD88-independent pathway also activates caspase-1 through adaptor molecule apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which in turn activates IL-1β, IL-18, and IL-33 from their corresponding precursors.34–37

Negative Regulation in TLR Signaling

  1. Top of page
  2. Abstract
  3. TLRs, Adaptor Molecules, and Signaling
  4. Negative Regulation in TLR Signaling
  5. Intracellular Recognition Receptors
  6. TLR Expression in the Liver
  7. TLR Signaling in Liver Disease
  8. TLRs and Infectious Liver Diseases
  9. Alcohol-Induced Liver Diseases
  10. NASH
  11. Hepatic Fibrosis
  12. HCV Infection
  13. HBV Infection
  14. Ischemia/Reperfusion Liver Injury
  15. Liver Regeneration
  16. HCC
  17. Hepatic Immune Disorders
  18. Perspectives
  19. Acknowledgements
  20. References

Excessive activation of TLR signaling may cause liver damage. Therefore, TLR signaling is strictly negatively regulated. ST2 (known as IL-33 receptor), single immunoglobulin IL-1R-related molecule (SIGGR/TIR8) and RP105 (a homolog of TLR4, essential for LPS recognition associated with MD-1 in B cells) negatively regulate TLR signaling at the receptor level.8, 38–40 Intracellular IRAK activity is suppressed by IRAK-M, suppressor of cytokine signaling-1 (SOCS-1), and Toll-interacting protein (Tollip).8, 41, 42 In addition, SOCS-1 degrades tyrosine-phosphorylated TIRAP to regulate TLR4 signaling.43 TGF-β prevents TLR4 signaling by the ubiquitination and degradation of MyD88.44 TRIF-dependent pathway is negatively regulated by TRAF1, phosphoinositide 3-kinase, SRC homology 2-domain-containing protein tyrosine phosphatase 2 (SHP2) and Sterile alpha and TIR-motif-containing 1 (SARM1/MyD88-5).45, 47–49 A20 restricts MyD88-dependent signaling and TRIF-dependent NF-κB activation, but not IRF3 activation.46, 50 RIP3 inhibits the TRIF-RIP1-NF-κB pathway.30 IRF4 impedes TLR signaling by competing with IRF5, but not with IRF7 for MyD88 interaction.51 Bcl-3 stabilizes NF-κBp50 by interfering ubiquitination of p50, which limits gene transcription to impair TLR responses.52, 53

Intracellular Recognition Receptors

  1. Top of page
  2. Abstract
  3. TLRs, Adaptor Molecules, and Signaling
  4. Negative Regulation in TLR Signaling
  5. Intracellular Recognition Receptors
  6. TLR Expression in the Liver
  7. TLR Signaling in Liver Disease
  8. TLRs and Infectious Liver Diseases
  9. Alcohol-Induced Liver Diseases
  10. NASH
  11. Hepatic Fibrosis
  12. HCV Infection
  13. HBV Infection
  14. Ischemia/Reperfusion Liver Injury
  15. Liver Regeneration
  16. HCC
  17. Hepatic Immune Disorders
  18. Perspectives
  19. Acknowledgements
  20. References

NOD Family Members.

NOD1 and NOD2, sense the cytosolic presence of the peptidoglycan fragments meso-diaminopimelic acid and muramyl dipeptide, respectively, driving the activation of mitogen-activated protein kinase (MAPK) and NF-κB and inducing caspase-1 activation in inflammasomes.54 Genetic variants of NOD2 are associated with Crohn's disease, but there is no evidence for a correlation with any liver diseases.

RNA Helicases.

Three cytosolic RNA helicases, retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated gene (MDA) 5, and LGP2 have been identified as intracellular recognition receptors.55, 56 RIG-I recognizes cytosolic uncapped single-stranded RNA bearing 5′-triphosphates generated by viral polymerases.57 MDA5 senses synthetic polyinosinic:polycytidylic acid (poly-I:C). LGP2 that lacks a caspase recruitment domain inhibits RIG-I and MDA5 signaling.58 Upon binding of ligand RNA, RIG-I and MDA5 bind through caspase recruitment domain to mitochondrial IPS-1 (also called MAVS, VISA, or Cardif), initiating signal cascades that lead to the activation of IRF3, IRF7, NF-κB, and AP-1, followed by type I IFN induction.59 RNA helicases are important for host defense against viral infection.56

TLR Expression in the Liver

  1. Top of page
  2. Abstract
  3. TLRs, Adaptor Molecules, and Signaling
  4. Negative Regulation in TLR Signaling
  5. Intracellular Recognition Receptors
  6. TLR Expression in the Liver
  7. TLR Signaling in Liver Disease
  8. TLRs and Infectious Liver Diseases
  9. Alcohol-Induced Liver Diseases
  10. NASH
  11. Hepatic Fibrosis
  12. HCV Infection
  13. HBV Infection
  14. Ischemia/Reperfusion Liver Injury
  15. Liver Regeneration
  16. HCC
  17. Hepatic Immune Disorders
  18. Perspectives
  19. Acknowledgements
  20. References

Kupffer Cells.

Kupffer cells, hepatic resident macrophages, are located in hepatic sinusoids and are the principal liver cells for phagocytosis, antigen presentation and the production of inflammatory cytokines. Because of the unique anatomical link between the liver and intestines, Kupffer cells are the first cell to encounter gut-derived toxins including LPS, but are less responsiveness by “LPS tolerance” under the physiological environment.5 Upon triggering, TLR4 signaling drives Kupffer cells to produce TNF-α, IL-1β, IL-6, IL-12, IL-18, and anti-inflammatory cytokine IL-10.34 Kupffer cell-derived IL-12 and IL-18 activate hepatic natural killer (NK) cells to increase the synthesis and release of antimicrobial IFNγ.60 Kupffer cells also express TLR2, TLR3, and TLR9.61–63 Moreover, Kupffer cells stimulate profibrogenic responses by the production of TGFβ1, matrix metalloproteinases, platelet-derived growth factor, and reactive oxygen species (ROS).5

Hepatocytes.

Hepatocytes may uptake and eliminate endotoxin from portal and systemic circulation.5 Primary cultured hepatocytes express mRNA for all TLRs and respond to TLR2 and TLR4 ligands, although more recent studies demonstrated that hepatocytes express very low levels of TLR2, TLR3, TLR4, and TLR5 and their responses are fairly weak in vivo.64–66

Hepatic Stellate Cells.

Hepatic stellate cells (HSCs) are located in the space of Disse and are the principal cellular source for the production of extracellular matrix proteins, such as collagen type I, III, and IV in the liver.67 HSCs express TLR4 and TLR9.66, 68, 69 TLR4 directly stimulates HSC to induce proinflammatory features, such as upregulation of chemokines (CCL2, CCL3, and CCL4) and adhesion molecules (vascular cell adhesion molecule 1 [VCAM-1], intercellular cell adhesion molecule 1 [ICAM-1], and E-selectin) and profibrogenic features including the enhancement of TGF-β signaling by the downregulation of TGF-β pseudoreceptor, bone morphogenetic protein and activin membrane bound inhibitor (Bambi), which leads to HSC activation.66, 68 TLR4 or TNF-α stimulation upregulates TLR2 expression in HSCs.66, 70 TLR9 signaling enhances collagen production in HSCs, but inhibits HSC migration, to modulate liver fibrosis.69

Biliary Epithelial Cells.

Biliary epithelial cells may contact enteric bacteria by the anatomical linking between the biliary system and the intestinal lumen. Therefore, immune responses should be controlled by “LPS tolerance.” Biliary epithelial cells express TLR2, TLR3, TLR4, and TLR5, and the stimulation of TLR2 and TLR4 increases IRAK-M expression to provide negative feedback on TLR signaling.71, 72

Liver Sinusoidal Endothelial Cells.

Hepatic sinusoids are lined by liver sinusoidal endothelial cells (LSEC) that express TLR4. Activating TLR4 results in NF-κB-induced production of TNF-α and ROS.73 The LSEC immune response is also modulated by “LPS tolerance.”73 Moreover, LPS-mediated LSEC damage is reduced in Kupffer cell-inactivated animals, suggesting little direct role of TLR4 in LSEC in vivo.74

Hepatic Dendritic Cells.

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) of the liver. Plasmacytoid DCs (pDCs, CD11c+B220+), but not conventional DCs (cDCs, CD11c+B220), are the principal cells that produce IFN-α in response to the ligands for TLR7 and TLR9, but not TLR4.75 Hepatic pDCs produce TNF-α, IL-6, and IL-12 by TLR7 and TLR9 stimulation.76 Hepatic cDCs produce TNF-α and IL-6 in response to the ligands for TLR2, TLR3, and TLR4.76 Both pDC and cDC subsets upregulate costimulatory molecules (CD40, CD80, and CD86) in response to TLR4, TLR7, and TLR9.75 Of note, hepatic DCs are hyperresponsive to TLR ligands to produce TNF-α, IL-6, and IL-12, but less capable of inducing TLR4-mediated and TLR9-mediated allogenic T cell proliferation compared with splenic DCs.76 Thus, hepatic DCs have unique properties that enable to induce strong innate responses with a lower capability of allostimulation.

Other Types of Immune Cells in the Liver.

Liver NK cells synthesize high amounts of IFN-γ in response to IL-12 synergistically with IL-18.77 Liver NK cells express TLR1, TLR2, TLR3, TLR4, TLR6, TLR7, and TLR9 and respond to corresponding TLR agonists synergistically with IL-12 to produce IFN-γ and chemokines, such as CCL3, CCL4, and CCL5.78 B cells proliferate by the activation of TLR2, TLR4, TLR7, and TLR9, but not TLR3, and TLRs are not required for antibody production.79 In general, T cells are indirectly activated by TLRs through APC-mediated IL-12 and IFN-α, which induce Th1 polarization.80 There is limited evidence that T cells directly respond to LPS to enhance their adhesion.81 A recent report showed that the activation of TLR modulates the lipid biosynthetic pathway in APCs, resulting in enhanced recognition of CD1d-associated lipids by invariant natural killer T (NKT) cells.82

TLR Signaling in Liver Disease

  1. Top of page
  2. Abstract
  3. TLRs, Adaptor Molecules, and Signaling
  4. Negative Regulation in TLR Signaling
  5. Intracellular Recognition Receptors
  6. TLR Expression in the Liver
  7. TLR Signaling in Liver Disease
  8. TLRs and Infectious Liver Diseases
  9. Alcohol-Induced Liver Diseases
  10. NASH
  11. Hepatic Fibrosis
  12. HCV Infection
  13. HBV Infection
  14. Ischemia/Reperfusion Liver Injury
  15. Liver Regeneration
  16. HCC
  17. Hepatic Immune Disorders
  18. Perspectives
  19. Acknowledgements
  20. References

Endotoxin-Induced Liver Injury.

Endotoxin-induced acute liver failure may result from endotoxin shock and is associated with a high mortality.77 Rodents are hyporesponsive to LPS compared with humans, so that heat-inactivated Propionibacterium acnes and D-galactosamine (D-GalN) are utilized to sensitizing rodents to LPS. The P. acnes-sensitized liver injury model is highly associated with the recruitment of macrophages and DCs, granuloma formation, and a polarization of Th1 in the liver.77 TLR9, TLR2, and MyD88 induce IFNγ, IL-12, and upregulation of TLR4 and MD-2 to prime P. acnes-elicited sensitization.83–85D-GalN sensitizes hepatocytes to TNF-α-mediated cell death. Upon sensitization, the ligands for TLR4, TLR2, TLR3, and TLR9 induce TNF-α-mediated liver damage.10, 13, 86 Pretreatment of LPS or lipoteichoic acid (LTA, TLR2 ligand) inhibits a second LPS or LTA challenge by “LPS/TLR-tolerance” or “cross-tolerance,” whereas CpG-DNA(TLR9 ligand) pretreatment protects only against secondary challenge of CpG-DNA and even enhances liver damage by a second LPS or LTA stimulation, suggesting that CpG-DNA induces the production of IFN-γ, which is involved in hepatocyte sensitization for a secondary challenge by a TLR2 and TLR4 ligand.86 TLR3 ligation impairs D-GalN/LPS-induced liver injury by downregulating TLR4 on macrophages.87 Treatment with a probiotic compound containing Bifidobacterium and Lactobacillus species prevents D-GalN/LPS-induced liver injury by the activation of peroxisome proliferator-activated receptor γ that modulates NF-κB activity.88 Furthermore, TLR9 ligand administration enhances cecal ligation and puncture-induced sepsis and liver injury.89 The deletion of NK and NKT cells attenuates this enhancement, suggesting a role for TLR9 on NK and/or NKT cells.89

TLRs and Infectious Liver Diseases

  1. Top of page
  2. Abstract
  3. TLRs, Adaptor Molecules, and Signaling
  4. Negative Regulation in TLR Signaling
  5. Intracellular Recognition Receptors
  6. TLR Expression in the Liver
  7. TLR Signaling in Liver Disease
  8. TLRs and Infectious Liver Diseases
  9. Alcohol-Induced Liver Diseases
  10. NASH
  11. Hepatic Fibrosis
  12. HCV Infection
  13. HBV Infection
  14. Ischemia/Reperfusion Liver Injury
  15. Liver Regeneration
  16. HCC
  17. Hepatic Immune Disorders
  18. Perspectives
  19. Acknowledgements
  20. References

TLRs play central roles in many microbial infections, including Listeria, Salmonella, and Plasmodium species. Listeria monocytogenes preferentially infects the liver and replicates in hepatocytes and Kupffer cells. Listeria-infected Kupffer cells secrete proinflammatory cytokines, such as TNF-α and IL-12 in a TLR2/MyD88-dependent manner.60 MyD88-deficient mice have a high mortality to infection with L. monocytogenes, because they do not mount the expected proinflammatory cytokine production and clearance.60, 90 In contrast, TLR2-deficient mice had lower levels of proinflammatory cytokines, but normal clearance, suggesting that TLR2 is involved in cytokine production, but multiple TLRs contribute to clearance against Listeria.60, 90

Salmonella typhimurium infection induces a TLR4-mediated NO-dependent antimicrobial response leading to granuloma formation and clearance by Kupffer cells.91, 92Salmonella choleraesuis infection induces TLR2-mediated Fas-ligand upregulation on NKT cells, which contributes to liver injury.93 However, eradication of S. choleraesuis is independent of TLR2 and TLR4. Notably, TLR9 stimulation inhibits intracellular growth of S. choleraesuis, suggesting multiple TLRs are involved in Salmonella infection.94

Malaria infection is a major life-threatening human disease in tropical regions. Human and mice have liver injury after infection by Plasmodium falciparum and Plasmodium berghei, respectively.95 Malaria-induced liver injury causes lymphocyte infiltration with hepatic cell death, which depends on IL-12 induced by TLR/MyD88-mediated signaling.95

Alcohol-Induced Liver Diseases

  1. Top of page
  2. Abstract
  3. TLRs, Adaptor Molecules, and Signaling
  4. Negative Regulation in TLR Signaling
  5. Intracellular Recognition Receptors
  6. TLR Expression in the Liver
  7. TLR Signaling in Liver Disease
  8. TLRs and Infectious Liver Diseases
  9. Alcohol-Induced Liver Diseases
  10. NASH
  11. Hepatic Fibrosis
  12. HCV Infection
  13. HBV Infection
  14. Ischemia/Reperfusion Liver Injury
  15. Liver Regeneration
  16. HCC
  17. Hepatic Immune Disorders
  18. Perspectives
  19. Acknowledgements
  20. References

Excessive alcohol intake changes the intestinal epithelial barrier causing increased intestinal permeability followed by elevated LPS levels in the portal circulation.96, 97 The LPS then activates TLR4 on Kupffer cells to produce proinflammatory cytokines, such as TNF-α, leading to hepatocyte damage. Indeed, treatment with lactobacillus or antibiotics suppresses alcohol-induced liver injury by changing enteric microflora.98, 99 Kupffer cell-inactivated animals, CD14-deficient, LBP-deficient, and TLR4-mutant mice have a strong reduction of liver injury despite elevated endotoxin levels.100–103 TLR4-induced ROS production in Kupffer cells is mediated by p47phox, the major component of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase during alcoholic liver injury.104 Chronic alcohol consumption upregulates hepatic TLR1, TLR2, TLR4, TLR6, TLR7, TLR8, TLR9, and CD14 mRNA expression and sensitizes to the corresponding TLR ligands to enhance TNF-α production.105, 106 Conversely, several reports showed that acute alcohol exposure suppresses TLR signaling. Ethanol administration interferes with the association of lipid rafts and TLR4/CD14 to suppress the activation of NF-κB and JNK and the production of TNF-α in macrophages.107, 108 Acute alcohol administration also decreases TLR3-mediated IL-6 and IL-12 production in response to poly-I:C in vivo.109 In contrast, acute alcohol augments TLR2 signaling.108

NASH

  1. Top of page
  2. Abstract
  3. TLRs, Adaptor Molecules, and Signaling
  4. Negative Regulation in TLR Signaling
  5. Intracellular Recognition Receptors
  6. TLR Expression in the Liver
  7. TLR Signaling in Liver Disease
  8. TLRs and Infectious Liver Diseases
  9. Alcohol-Induced Liver Diseases
  10. NASH
  11. Hepatic Fibrosis
  12. HCV Infection
  13. HBV Infection
  14. Ischemia/Reperfusion Liver Injury
  15. Liver Regeneration
  16. HCC
  17. Hepatic Immune Disorders
  18. Perspectives
  19. Acknowledgements
  20. References

NASH is characterized by lipid accumulation in hepatocytes and inflammatory cell infiltration, which leads to hepatic fibrosis. A methionine/choline-deficient (MCD) diet is widely used as an animal model of NASH. MCD diet-induced NASH enhances susceptibility to TLR4 ligand LPS, but not TLR2 ligand peptidoglycan, to produce inflammatory cytokines.110 The loss of TLR4 attenuated hepatic lipid accumulation and hepatic mRNA levels of fibrogenic markers, such as collagen α1(I) and TGF-β1 in MCD diet-induced steatohepatitis, indicating the importance of TLR4 in NASH.111 In contrast to TLR4, TLR2-deficiency does not protect against MCD diet-induced steatohepatitis.110 Leptin- or leptin receptor-deficient animals that are genetically obese, are highly susceptible to LPS and develop steatohepatitis after low dose of LPS administration.112 Probiotics diminish NASH in leptin-deficient ob/ob mice, suggesting a link between enteric flora and liver injury.113, 114 In addition, high-fat diet feeding alters the content of gut microflora and increases plasma LPS level to induce “metabolic endotoxemia,” causing hepatic fat accumulation and insulin resistance.115

Hepatic Fibrosis

  1. Top of page
  2. Abstract
  3. TLRs, Adaptor Molecules, and Signaling
  4. Negative Regulation in TLR Signaling
  5. Intracellular Recognition Receptors
  6. TLR Expression in the Liver
  7. TLR Signaling in Liver Disease
  8. TLRs and Infectious Liver Diseases
  9. Alcohol-Induced Liver Diseases
  10. NASH
  11. Hepatic Fibrosis
  12. HCV Infection
  13. HBV Infection
  14. Ischemia/Reperfusion Liver Injury
  15. Liver Regeneration
  16. HCC
  17. Hepatic Immune Disorders
  18. Perspectives
  19. Acknowledgements
  20. References

Hepatic fibrosis and subsequent cirrhosis results from chronic liver injury, which may be caused by excessive alcohol consumption, hepatitis B and C, autoimmune hepatitis, biliary obstruction, or NASH.67 Portal LPS concentration is elevated in patients with cirrhosis, suggesting that increased intestinal permeability allows microflora-derived LPS into the portal vein. Several studies have demonstrated that modulation of the gut flora in advanced cirrhosis by probiotics or antibiotics is beneficial for the prevention of bacterial translocation and spontaneous bacterial peritonitis.116–120 Recently, we and others showed that CD14, LBP, TLR4, and MyD88 is critical for hepatic fibrogenesis induced by bile duct ligation and CCl4 in mice.17, 66, 121 TLR4 is expressed on two key cells involved in hepatic fibrosis, Kupffer cells and HSCs (Fig. 2). TLR4 signaling was considered to initiate fibrogenesis by proinflammatory and profibrogenic cytokines from Kupffer cells, which then activated HSCs.67 Our recent study showed that chimeric mice that contain TLR4-mutant Kupffer cells and TLR4-intact HSCs developed significant fibrosis and the mice that contain TLR4-intact Kupffer cells and TLR4-mutant HSCs developed minimal fibrosis after bile duct ligation, indicating that TLR4 on HSCs, but not Kupffer cells is crucial for hepatic fibrosis.66 Notably, Kupffer cells are essential for fibrosis by producing TGF-β independent of TLR4.66 TLR4-activated HSCs produce chemokines (CCL2, CCL3, and CCL4) and express adhesion molecules (ICAM-1 and VCAM-1) that recruit Kupffer cells to the site of injury. Simultaneously, TLR4 signaling downregulates the TGF-β decoy receptor, Bambi to boost TGF-β signaling leading to hepatic fibrosis.66 A recent whole genome scan in chronic HCV patients has identified a single nucleotide polymorphism in TLR4 that reduces TLR4 activity to confer a reduced risk of developing hepatic fibrosis, thus confirming the relevance of TLR4 in a large group of patients with hepatic fibrosis.122 Although TLR2 plays no significant role in hepatic fibrosis in vivo, TLR2 is dramatically upregulated in HSCs in response to LPS or TNF-α, implying a potential role of TLR2 ligands such as HCV core and NS3 protein in HSC activation.66, 70, 123, 124 HSCs also express TLR9. Endogenous DNA from damaged hepatocytes activates HSCs to produce collagen, but suppresses HSC chemotaxis through TLR9.69 The injection of TLR3 ligand poly-I:C inhibits HSC activation by IFN-γ from NK cells, which attenuates hepatic fibrosis.125 Notably, chronic ethanol consumption abolishes the antifibrotic effects of TLR3, implicating the mechanism by which alcohol accelerates liver fibrosis.126

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Figure 2. Fibrogenic signals are enhanced by TLR4 in HSCs. Upon liver injury, gut flora-derived LPS stimulates TLR4 on HSCs followed by chemokine production and downregulating TGFβ pseudoreceptor, bone morphogenetic protein and activin membrane bound inhibitor (Bambi). Simultaneously, Kupffer cells produce TGF-β1, which stimulates unrestricted TGF-β receptor signaling on HSCs leading to fibrosis.

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HCV Infection

  1. Top of page
  2. Abstract
  3. TLRs, Adaptor Molecules, and Signaling
  4. Negative Regulation in TLR Signaling
  5. Intracellular Recognition Receptors
  6. TLR Expression in the Liver
  7. TLR Signaling in Liver Disease
  8. TLRs and Infectious Liver Diseases
  9. Alcohol-Induced Liver Diseases
  10. NASH
  11. Hepatic Fibrosis
  12. HCV Infection
  13. HBV Infection
  14. Ischemia/Reperfusion Liver Injury
  15. Liver Regeneration
  16. HCC
  17. Hepatic Immune Disorders
  18. Perspectives
  19. Acknowledgements
  20. References

HCV causes chronic liver inflammation and fibrosis, resulting in cirrhosis and hepatocellular carcinoma (HCC). HCV evades the host immune system to sustain a chronic infection (Fig. 3). HCV interferes with signals of the (1) TLR3-TRIF-TBK1-IRF-3 pathway, (2) TLR-MyD88 pathway, and (3) RIG-I/MDA5-IPS-1 pathway. NS3/4a interacts with TBK1 to prevent the association between TBK1 and IRF3. NS3 induces degradation of TRIF, interrupting IRF3 activation and IFN-β production.127, 128 Macrophages overexpressing NS3, NS3/4A, NS4B, or NS5A showed a strong suppression of TLR2, TLR4, TLR7, and TLR9 signalings.129 NS5A interacts with MyD88 to prevent IRAK1 recruitment and cytokine production, such as IL-1, IL-6, and IFN-β in response to the ligands for TLR2, TLR4, TLR7, and TLR9.129 While HCV infection transiently induces RIG-I-IPS-1-dependent IRF3 activation followed by IFN-β production, NS3/4A cleavages of IPS-1 at C508, releasing IPS-1 from the mitochondrial membrane.58, 130–132 Cleaved IPS-1 results in loss of interaction with RIG-I preventing IRF-3 activation and IFN-β production, which ultimately interrupts HCV eradication.131 Alternatively, NS5A upregulates TLR4 expression in B cells and hepatocytes to augment TLR4 signaling.133 HCV core and NS3 proteins activate TLR2 associated with TLR1 and TLR6 in monocytes to induce TNFα, IL-6, and IL-8 production.123, 134 In contrast, monocytes from chronic HCV patients lack LPS-induced tolerance with a second challenge with TLR ligands and lack HCV core-mediated tolerance with a second stimulation with HCV core protein.135 This mechanism may sustain inflammation in chronic HCV infection. pDCs from HCV patients have reduced HLA-DR and IFN-β production in response to TLR7 ligand, which is associated with impaired activation of naive CD4 T cells.136 In contrast, CD4 T cell-activation by myeloid DC with TLR3 ligation does not differ between HCV-infected and healthy control subjects.136 Similarly, infectious cell culture-produced HCV inhibits TLR9-mediated IFN-α production in pDCs, but does not alter TLR3-mediated and TLR4-mediated IL-12, IL-6, IL-10, IFN-γ, and TNF-α production in myeloid DCs.137 Thus, HCV activates innate immune systems and simultaneously has multiple methods to escape from host immunity to sustain a chronic infection. Recent studies have shown the potential role of TLR7 and TLR9 agonist for anti-HCV therapy.138, 139

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Figure 3. HCV stimulates innate immune signaling in a positive and negative fashion. HCV could stimulate TLR2 and cytosolic RIG-I. HCV (NS3/4A and NS3) degrades TRIF and binds to TBK1, which inhibits IFN-β production. HCV (NS5A) binds to MyD88 to prevent TLR2, 4, 7, and 9-mediated signaling. HCV (NS3/4A) cleaves of IPS-1 at C508, releasing IPS-1 from mitochondria resulting in preventing IRF3-dependent IFN-β production.

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HBV Infection

  1. Top of page
  2. Abstract
  3. TLRs, Adaptor Molecules, and Signaling
  4. Negative Regulation in TLR Signaling
  5. Intracellular Recognition Receptors
  6. TLR Expression in the Liver
  7. TLR Signaling in Liver Disease
  8. TLRs and Infectious Liver Diseases
  9. Alcohol-Induced Liver Diseases
  10. NASH
  11. Hepatic Fibrosis
  12. HCV Infection
  13. HBV Infection
  14. Ischemia/Reperfusion Liver Injury
  15. Liver Regeneration
  16. HCC
  17. Hepatic Immune Disorders
  18. Perspectives
  19. Acknowledgements
  20. References

Hepatitis B virus is self-limited in more than 90% of adults. The remaining patients develop chronic hepatitis that may result in cirrhosis and HCC. A series of studies using HBV transgenic mice revealed the critical role of HBV-specific CD8+ cytotoxic T cell and CD4+ helper T cell and IFN-γ in HBV replication in vivo.140, 141 The injection of ligands for TLR3, TLR4, TLR5, TLR7, and TLR9 suppress HBV replication in an IFN-α/β-dependent manner in HBV transgenic mice.65 These antiviral effects of TLR ligands are directed at nonparenchymal cells, but not hepatocytes that express low level of TLRs. Further experiments demonstrated that nonparenchymal cell-derived mediators inhibit HBV replication in HBV-Met cells.62 The supernatants from TLR3-stimulated Kupffer cells and LSECs and TLR4-stimulated Kupffer cells inhibit HBV replication independently of MyD88 in vitro, suggesting that TRIF-dependent IFN-β plays a role.62 Additionally, the agonists for TLR7 and TLR9 augment the immunogenicity of HBV vaccination, suggesting that TLR agonists may become a beneficial treatment for chronic HBV infection and vaccination.142, 143

Ischemia/Reperfusion Liver Injury

  1. Top of page
  2. Abstract
  3. TLRs, Adaptor Molecules, and Signaling
  4. Negative Regulation in TLR Signaling
  5. Intracellular Recognition Receptors
  6. TLR Expression in the Liver
  7. TLR Signaling in Liver Disease
  8. TLRs and Infectious Liver Diseases
  9. Alcohol-Induced Liver Diseases
  10. NASH
  11. Hepatic Fibrosis
  12. HCV Infection
  13. HBV Infection
  14. Ischemia/Reperfusion Liver Injury
  15. Liver Regeneration
  16. HCC
  17. Hepatic Immune Disorders
  18. Perspectives
  19. Acknowledgements
  20. References

Ischemia and reperfusion (I/R) injury of the liver transiently occurs in the procedures during liver transplantation, partial hepatectomy (PH), hypovolemic shock, and trauma. Kupffer cells play a prominent role in I/R liver injury. The pathophysiological changes of I/R injury include LSEC disruption, hepatocyte necrosis, and activating inflammatory cells including neutrophils and Kupffer cells. Upon I/R injury, the endogenous TLR4 ligand HMGB1 is released from damaged hepatocytes and subsequently stimulates nonparenchymal cells including Kupffer cells through TLR4.14, 144 HMGB1 release from hepatocytes depends on oxidative stress that also requires TLR4 signaling.145 The positive loop of HMGB1-TLR4 signaling may encourage a sustained inflammatory response in the liver after I/R. In contrast to other models of liver diseases, MyD88 plays no role in I/R liver injury.146 Activated TLR4 transmits its signal to IRF3 through TRIF to produce IFN-β, subsequently inducing chemokine (C-X-C motif) ligand (CXCL)10 production through the type I IFN receptor, which eventually contributes to I/R liver injury.146–148 Elevated HO-1 levels in TLR4-deficient mice are involved in the protection from I/R injury.149 These studies were extended to investigate the role of TLR4 in liver transplantation. Either wild-type or TLR4-deficient recipients that were transplanted with TLR4-deficient liver, but not wild-type liver, exhibited less I/R injury characterized by the reduction of hepatocyte damage, neutrophil infiltration and the expression of CXCL10, ICAM-1, and TNF-α, and the elevation of HO-1 expression.150 TLR4-mediated signaling also participates in the accumulation of circulating CD8+ T cells into the liver in liver transplantation.151

Liver Regeneration

  1. Top of page
  2. Abstract
  3. TLRs, Adaptor Molecules, and Signaling
  4. Negative Regulation in TLR Signaling
  5. Intracellular Recognition Receptors
  6. TLR Expression in the Liver
  7. TLR Signaling in Liver Disease
  8. TLRs and Infectious Liver Diseases
  9. Alcohol-Induced Liver Diseases
  10. NASH
  11. Hepatic Fibrosis
  12. HCV Infection
  13. HBV Infection
  14. Ischemia/Reperfusion Liver Injury
  15. Liver Regeneration
  16. HCC
  17. Hepatic Immune Disorders
  18. Perspectives
  19. Acknowledgements
  20. References

The liver has potent regenerative properties after massive loss of hepatic parenchymal cells upon liver injury or hepatic resection.152 The signals transmitted by cytokines (TNF-α and IL-6) and growth factors (HGF, EGF, HB-EGF, and TGF-α) and subsequent activation of transcription factors (AP-1, NF-κB, and Stat3) are important components for hepatocyte replication during liver regeneration.152 PH increases portal LPS levels that may contribute to triggering liver regeneration.152 This observation led to the hypothesis that TLRs trigger the secretion of TNF-α and IL-6 by Kupffer cells in the initiation of liver regeneration. MyD88 plays a crucial role in the activation of NF-κB, followed by the induction of TNF-α, IL-6, and early immediately genes, such as c-myc, c-fos, and c-jun during liver regeneration after PH.152–154 However, this cytokine production through the TLR/MyD88 pathway may only contribute to the early phase of liver regeneration.152, 153 Moreover, we did not find a requirement for TLR2, TLR4, or TLR9 in liver regeneration after PH,152–154 despite the role of TLR4 in liver regeneration after CCl4 administration.155 NF-κB is a key transcription factor activated by TLR/MyD88 and TNF-α signaling. Inactivation of NF-κB in hepatocytes does not impair liver regeneration.156, 157 These observations further support the concept that TLR/MyD88 signaling activated in Kupffer cells produces proliferative mediators that contribute to liver regeneration. Collectively, TLR/MyD88 signaling may trigger the production of inflammatory cytokines, such as TNF-α and IL-6, in the first step of liver regeneration, but current studies have not identified the exact TLRs and ligands that initiate the cytokine cascade in liver regeneration.152 On the other hand, injection of TLR4 ligand LPS or TLR3 ligand poly-I:C suppresses liver regeneration after PH, indicating that excessive TLR signaling may also inhibit liver regeneration.158, 159

HCC

  1. Top of page
  2. Abstract
  3. TLRs, Adaptor Molecules, and Signaling
  4. Negative Regulation in TLR Signaling
  5. Intracellular Recognition Receptors
  6. TLR Expression in the Liver
  7. TLR Signaling in Liver Disease
  8. TLRs and Infectious Liver Diseases
  9. Alcohol-Induced Liver Diseases
  10. NASH
  11. Hepatic Fibrosis
  12. HCV Infection
  13. HBV Infection
  14. Ischemia/Reperfusion Liver Injury
  15. Liver Regeneration
  16. HCC
  17. Hepatic Immune Disorders
  18. Perspectives
  19. Acknowledgements
  20. References

HCC is a major complication in the end-stage of cirrhosis. There is increasing evidence for TLRs playing a role in hepatocarcinogenesis. The chemical carcinogen, diethylnitrosamine, causes inflammation-associated liver cancer in mice. Mice deficient in TLR4 and MyD88, but not TLR2, have a marked decrease in the incidence, size, and number of chemical-induced liver cancer, indicating a strong contribution of TLR signaling to hepatocarcinogenesis (Seki, unpublished observation).17 Clinical and epidemiological evidence implicates long-term alcohol consumption in accelerating HCV-mediated tumorigenesis. HCV NS5A transgenic mice with long-term alcohol feeding develop typical tumors associated with NS5A-mediated TLR4 overexpression in the liver.160 Collectively, TLR4-MyD88 signaling appears to be essential for hepatocarcinogenesis.

Hepatic Immune Disorders

  1. Top of page
  2. Abstract
  3. TLRs, Adaptor Molecules, and Signaling
  4. Negative Regulation in TLR Signaling
  5. Intracellular Recognition Receptors
  6. TLR Expression in the Liver
  7. TLR Signaling in Liver Disease
  8. TLRs and Infectious Liver Diseases
  9. Alcohol-Induced Liver Diseases
  10. NASH
  11. Hepatic Fibrosis
  12. HCV Infection
  13. HBV Infection
  14. Ischemia/Reperfusion Liver Injury
  15. Liver Regeneration
  16. HCC
  17. Hepatic Immune Disorders
  18. Perspectives
  19. Acknowledgements
  20. References

Innate immunity, especially TLR signaling, is associated with autoimmune diseases that are the consequence of the excessive immune response to self. There is increasing evidence for TLR signaling in the pathogenesis of PBC, primary sclerosing cholangitis (PSC), and autoimmune hepatitis. TLR3, TLR4, TLR9, and RP105 expressions are significantly elevated in PBC patients.161–164 Monocytes from PBC patients appear more sensitive to the ligands for TLR2, TLR3, TLR4, TLR5, and TLR9, producing higher levels of proinflammatory cytokines.165 B cells from PBC patients express high levels of TLR9. CpG-B stimulation induces high level of intracellular immunoglobulin M and antimitochondrial antibodies.163, 166 A single nucleotide polymorphism in TLR9 induces higher expression of intracellular immunoglobulin M in response to CpG-B in B cells.167 PSC is characterized by the destruction of hepatic bile duct and a high frequency of antibiliary epithelial cell antibodies (anti-BEC-Ab). Anti-BEC-Ab-stimulated BECs or PSC patient-derived BECs that express higher levels of TLR4 and TLR9, respond to ligands for TLR4 and TLR9 to produce higher levels of inflammatory cytokines.168 Lymphocytic choriomeningitis virus infection induces a model of autoimmune hepatitis in mice through TLR3 on APCs including macrophages and DCs. Upon TLR3 ligation, IFN-α/β, TNF-α, and CXCL9 are released, which recruit CD8+ T cells causing liver damage.169

Perspectives

  1. Top of page
  2. Abstract
  3. TLRs, Adaptor Molecules, and Signaling
  4. Negative Regulation in TLR Signaling
  5. Intracellular Recognition Receptors
  6. TLR Expression in the Liver
  7. TLR Signaling in Liver Disease
  8. TLRs and Infectious Liver Diseases
  9. Alcohol-Induced Liver Diseases
  10. NASH
  11. Hepatic Fibrosis
  12. HCV Infection
  13. HBV Infection
  14. Ischemia/Reperfusion Liver Injury
  15. Liver Regeneration
  16. HCC
  17. Hepatic Immune Disorders
  18. Perspectives
  19. Acknowledgements
  20. References

Although the liver is constantly exposed to low levels of gut-derived microbial products, the innate immune systems has adapted strategies to prevent TLR activation and harmful responses under physiological circumstances. Our current hypothesis is that TLR activation and liver injury are preceded by changes of the intestinal permeability and commensal intestinal microflora in diseases such as alcoholic liver diseases, NASH, and hepatic fibrosis. Intestinal permeability is increased by the following condition: the destruction of intestinal mucosa or tight junction dysfunction due to excessive alcohol intake, the increased portal pressure in cirrhosis or the hyperdynamic status of portal circulation in acute inflammatory liver diseases. Thus, TLR signaling in the liver links the gut flora to immune responses. Gut sterilization by antibiotics attenuates pathological changes in many models of liver diseases. However, long-term antibiotic treatment may alter the distribution of beneficial commensal flora and increases the risk of inflammatory bowel disease.170 Moreover, recent evidence suggests the contribution of endogenous TLR ligands, such as HMGB1 and the products from dying cells, to liver disease. Here we propose the concept that gut flora-mediated TLR responses further contribute to the release of endogenous TLR ligand, which repeatedly stimulates TLRs and augments innate immune responses in the liver. Models using germ-free animals and the studies on endogenous TLR ligands will provide new insights into the role of exogenous and endogenous ligands. Under many pathophysiological circumstances, TLRs act as a double-edged sword. Adequate strength of TLR signaling induces “beneficial” responses, such as microorganism clearance, regenerative responses, protection from cell death, and adjuvants for vaccination. In contrast, excessive TLR signaling and TLR signaling in a perturbed microenvironment triggers “harmful” responses, such as endotoxin shock, multiple organ failure, suppression of regenerative responses, and induction of cell death, fibrosis, and cancer. More studies in animal models are needed to translate TLR pathophysiology into clinical practice in human liver diseases. Modifying gut flora by using probiotics may become a novel therapeutical strategy for liver diseases, and TLRs and their downstream signaling molecules may become pharmacological targets in liver disease.

References

  1. Top of page
  2. Abstract
  3. TLRs, Adaptor Molecules, and Signaling
  4. Negative Regulation in TLR Signaling
  5. Intracellular Recognition Receptors
  6. TLR Expression in the Liver
  7. TLR Signaling in Liver Disease
  8. TLRs and Infectious Liver Diseases
  9. Alcohol-Induced Liver Diseases
  10. NASH
  11. Hepatic Fibrosis
  12. HCV Infection
  13. HBV Infection
  14. Ischemia/Reperfusion Liver Injury
  15. Liver Regeneration
  16. HCC
  17. Hepatic Immune Disorders
  18. Perspectives
  19. Acknowledgements
  20. References