Toll-Like Receptor Signaling in the Liver

Schematic overview of TLR signaling pathways. Viral PAMPS activate TLR3, TLR7, and TLR9, whereas bacterial PAMPs activate TLR1, TLR2, TLR4, TRL6, and TLR9. Each receptor interacts with 1 or several adapter molecules (MyD88, TRIF, TRAM, and TIRAP) to then induce activation of 1 or several downstream kinases and transcription factors, which up-regulate proinflammatory, antiviral, and antibacterial mediators. The main signaling pathways induced are the IRF7-IFN pathway (green), IRF3-IFN pathway (light blue), NF-κB pathway (red), AP-1 pathway (red), IRF5 pathway (dark blue), and p38 pathway (orange).

Negative regulation of TLR signaling. TLR signaling is negatively regulated at several levels. At the receptor level, the TIR domain containing receptors ST2 and SIGGIR sequester signaling molecules and inhibit TLR4 signaling. The ubiquitin ligase TRIAD3A induces the degradation of TLR4 and TLR9. At the level of adapater molecules, MyD88s blocks the recruitment of IRAK4. At the level of receptor proximal kinases, the IRAK family member IRAK-M and the splice variants of IRAK2, IRAK2c, and 2d, inhibit IRAK activity. SOCS1 inhibits NF-κB, JNK, and p38 activation, which are at least in part mediated by effects of IRAK.

TLR signaling in alcoholic liver injury. Orally ingested alcohol destroys the intestinal barrier and increases the levels of LPS in the portal vein. LPS binds to TLR4, which is expressed on Kupffer cells. TLR4 activated NF-κB, JNK/AP-1, and NADPH oxidase. These factors are involved in the release of TNF-α, IL-1β, IL-12, and IL-18, which then promote hepatocyte injury through the recruitment of neutrophils and platelets and through direct effects on hepatocytes.

TLR signaling in hepatic fibrogenesis. During liver injury, LPS levels are increased because of increased permeability of the intestinal mucosal barrier. Toll-like signaling may contribute to fibrogenesis through 2 pathways: (1) LPS stimulate TLR4 on Kupffer cells to (a) enhance hepatocyte damage, (b) increase leukocyte infiltration, and (c) secrete profibrogenic cytokines such as TGF-β and PDGF. These factors are believed to then act in concert to induce activation of hepatic stellate cells and fibrogenesis. (2) LPS may directly stimulate TLR4 on hepatic stellate cells to activate NF-κB and JNK and perpetuate hepatic stellate cell activation. In patients with hepatitis C, HCV-NS3, and HCV-core, may act as TLR2 ligands and activate proinflammatory and profibrogenic pathways in Kupffer cells and HSCs.

Effects of HCV on TLR signaling. Double-stranded RNA from HCV binds to TLR3. However, TLR3 signaling is inhibited by NS3/4A through degradation of TRIF and by NS3 by binding to TBK1 and blocking the association between TBK1 and IRF3. HCV mediates activation of NF-κB, JNK/AP-1, and p38 through a TLR2-MyD88-IRAK pathway.

Dual role of Toll-like receptor signaling in liver injury. After ischemia or partial hepatectomy, TLR ligands increase to activate Kupffer cells. In the case of liver regeneration, a modest amount of TLR stimulation induces NF-κB and AP-1 activation in the Kupffer cells, which leads to IL-6 and TNF-α secretion and a regenerative hepatocyte response. Strong TLR stimulation, eg, after ischemia-reperfusion injury, leads to the activation of cytotoxic mediators, which directly and indirectly cause hepatocyte injury.