Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut

Abstract

Liver fibrosis occurs as a wound-healing scar response following chronic liver inflammation including alcoholic liver disease, non-alcoholic steatohepatitis, viral hepatitis, cholestatic liver disease and autoimmune liver diseases. The liver has a unique vascular system within the gastrointestinal tract, as the majority of the liver's blood supply comes from the intestine through the portal vein. When the intestinal barrier function is disrupted, an increase in intestinal permeability leads to the translocation of intestine-derived bacterial products such as lipopolysaccharide (LPS) and unmethylated CpG containing DNA to the liver via the portal vein. These gut-derived bacterial products stimulate innate immune receptors, namely Toll-like receptors (TLRs), in the liver. TLRs are expressed on Kupffer cells, endothelial cells, dendritic cells, biliary epithelial cells, hepatic stellate cells, and hepatocytes. TLRs activate these cells to contribute to acute and chronic liver diseases. This review summarizes recent studies investigating the role of TLRs, intestinal microbiota and bacterial translocation in liver fibrosis, alcoholic liver disease and non-alcoholic steatohepatitis.

Figures

Figure 1. Overview of TLR signalling

TLR1, TLR2, TLR4, TLR5 and TLR6 are expressed on cell membrane. TLR3, TLR7/8 and TLR9 are expressed in endosome. All TLRs except for TLR3 activate MyD88-dependent pathway to induce NF-κB and p38/JNK activation. TLR2 and TLR4 signalling require TIRAP and MyD88. TLR3 requires TRAF to activate TBK1/IKKɛ. After TLR4 internalization, TLR4 signalling activates TRAM/TRIF-dependent pathway. TLR3/4-dependent TRIF-dependent signalling induces IRF-3 activation and IFN-β production. TLR7/8 and TLR9 induce IFN-α production through IRF7.

Figure 2. TLR4 signalling in hepatic stellate cells during liver fibrosis

In chronic liver damage, intestinal permeability is increased due to systemic inflammation, portal hypertension, intestinal dysbiosis or tight junction disintegrity, which allows translocation of gut microflora-derived LPS into the liver through the portal vein. Translocated LPS stimulates TLR4 on hepatic stellate cells (HSCs). High expression of Bambi prevents TGF-β signalling in quiescent HSCs. Upon activation of TLR4, HSCs produce chemokines (MCP-1, MIP-1β and RANTES) that recruit Kupffer cells through CCR1 and CCR2. TLR4-activated HSCs downregulate Bambi and increase its sensitivity to TGF-β released from Kupffer cells. The fully activated TGF-β signalling then induces HSC activation. TLR4 signalling-mediated Bambi downregulation requires MyD88 and NF-κB.

Figure 3. Bacterial translocation and hepatic TLR4 signalling in alcoholic liver disease

Excessive intake of alcohol induces changes in composition of intestinal microflora and bacterial overgrowth. In addition, tight junction disruption causes an increase in intestinal permeability, leading to translocation of gut microflora-derived LPS into the liver through the portal vein. Translocated LPS stimulates TLR4 on both Kupffer cells and hepatic stellate cells (HSCs). Upon activation of TLR4, Kupffer cells and HSCs produce chemokines (MCP-1, MIP-1α, MIP-1β and RANTES) that recruit Kupffer cells as well as HSCs. This activation of cells participates in liver inflammation, hepatocyte steatosis and fibrosis.