Toll-like receptors as targets in chronic liver diseases

Abstract

Toll-like receptors (TLRs) recognise pathogen-associated molecular patterns (PAMPs) to detect the presence of pathogens. In addition to their role in innate immunity, TLRs also play a major role in the regulation of inflammation, even under sterile conditions such as injury and wound healing. This involvement has been suggested to depend, at least in part, on the ability of TLRs to recognise several endogenous TLR ligands termed damage-associated molecular patterns (DAMPs). The liver not only represents a major target of bacterial PAMPs in many disease states but also upregulates several DAMPs following injury. Accordingly, TLR-mediated signals have been implicated in a number of chronic liver diseases. Here, we will summarise recent findings on the role TLRs and TLR ligands in the pathophysiology of liver fibrosis and cirrhosis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease and hepatocellular carcinoma, and highlight the potential role of TLR agonists, antagonists and probiotics for the treatment of chronic liver disease.

Figure 1. TLR signaling

TLRs that are predominantly activated by viral PAMPS are located within the endosome whereas TLRs that are predominantly activated by bacterial PAMPS are located on the cell surface. In addition to PAMPs, several endogenous mediators including hyaluronan and HMGB1 have been suggested to activate TLR2 and TLR4. TLRs mediate their signaling through two adapter molecules, MyD88 and Trif to induce up-regulation proin ammatory and antiviral genes. MyD88-induced signals (marked in orange) predominantly activate NF-κB, IRF-7 and JNK, Trif-dependent signals (marked in blue) predominantly activate NF-κB and IRF-3 (adapted from Schwabe et al, Gastroenterology 130:1886–900).

Figure 2. Prevention of bacterial translocation by the intestinal epithelial barrier

Under normal circumstances, a number of protective mechanisms at different levels ensure that only a minimal amount of bacterial transloction occurs: (i) Luminal factors such as the predominance of anaerobic bacteria which limit the growth and translocation of aerobic and facultative anaerobic bacteria; (ii) bile inhibits bacterial overgrowth; (iii) IgA prevents microbial entry and transports IgA-bound microbes from the lamina propria back to the lumen (iv) a thick mucus layer prevents bacterial contact and attachment (v) intact tight junctions prevent paracellular penetration (vi) the mucosa-associated lymphatic tissue (MALT) phagocytoses translocating bacteria. (adapted from Wiest et al., Hepatology 2005; 41:422–33.)

Figure 3. Promotion of alcoholic liver injury by an LPS-TLR4 signaling cascade

Orally ingested alcohol increase intestinal permeability leading to increased levels of LPS in the portal vein. In the liver, LPS binds to TLR4 on Kupffer cells to activate NF-κB, and NADPH oxidase, through a MyD88-independent pathway. Release of cytokine by Kupffer cells promotes hepatocyte injury through the recruitment of neutrophils through direct effects on hepatocytes.

Figure 4. Promotion of hepatic stellate cell activation and fibrosis by LPS

Following liver injury, alterations in the bacterial microbiota and the intestinal mucosal barrier cause an increase in the translocation of LPS. LPS directly targets quiescent hepatic stellate cells resulting in (i) downregulation of the TGFβ pseudoreceptor Bambi and (ii) upregulation of chemokines. These two signals complement each other to promote hepatic stellate cell activation: 1. Downregulation of Bambi through a TLR4-MyD88-NF-κB signaling cascade sensitizes hepatic stellate cells towards the effect of TGFβ. 2. Chemokines induce Kupffer cells, a main source of TGFβ in the injured liver, to migrate towards hepatic stellate cells. Together, these two mechanisms allow TGFβ-dependent activation of hepatic stellate cell by Kupffer cells resulting in increased deposition of extracellular matrix and liver fibrosis.

Figure 5. Positive and negative regulation of TLR signaling by HCV

Double-stranded RNA from HCV binds to TLR3 within the endosome. However, efficient TLR3 signaling is prevented by 2 mechanisms: (i) Degradation of Trif by HCV NS3/4A and (ii) by NS3 by binding to TBK1 and blocking the association between TBK1 and IRF3. Moreover, HCV NS5A also blocks TLR9-induced levels at the level of MyD88. The interference of HCV with these anti-viral pathways HCV prevents eradication of HCV by the immune system. At the same time, some HCV proteins promote inflammatory signals through TLR2 and TLR4. These may be dampened by inhibition of MyD88 signaling by HCV NS3 but are likely to contribute to chronic inflammation and potentially the progression to fibrosis and cirrhosis. (Figure based on [8]).