Toll-like receptor signaling and liver fibrosis

Abstract

Liver fibrosis occurs as a wound-healing scar response following acute and chronic liver inflammation including alcoholic liver disease, non-alcoholic steatohepatitis, hepatitis B and C, and autoimmune hepatitis. Myofibroblasts, mainly transdifferentiated from hepatic stellate cells, are pivotal cell types that produce fibrillar collagen. The activation of inflammatory cells, including Kupffer cells, is a crucial step for activating hepatic stellate cells. Toll-like receptors (TLRs) are pattern recognition receptors that sense pathogen-associated molecular patterns (PAMPs), which discriminate the products of microorganisms from the host. TLRs are expressed on Kupffer cells, endothelial cells, dendritic cells, biliary epithelial cells, hepatic stellate cells, and hepatocytes in the liver. TLR signaling induces potent innate immune responses in these cell types. The liver is constantly exposed to PAMPs, such as LPS and bacterial DNA through bacterial translocation because there is a unique anatomical link, the portal vein system between liver and intestine. Recent evidence demonstrates the role of TLRs in the activation of hepatic immune cells and stellate cells during liver fibrosis. Moreover, crosstalk between TLR4 signaling and TGF-beta signaling in hepatic stellate cells has been reported. This paper highlights the role of TLR signaling in stellate cell activation and the progression of liver fibrosis.

Figure 1

TLR4 signaling enhances TGF-β signaling in hepatic stellate cells. Upon liver injury, intestinal permeability is increased due to the intestinal dysbiosis and tight junction disintegrity, which allows microflora-derived LPS into the portal vein. This LPS stimulates TLR4 on hepatic stellate cells (HSCs). Quiescent HSCs express high levels of Bambi which restricts TGF-β signaling. TLR4 stimulation leads to the production of various chemokines (MCP-1, MIP-1β, and RANTES) in HSCs, recruiting Kupffer cells through their CCR1 and CCR2. Recruited Kupffer cells produce TGF-β which binds to TGF-β receptor type I in HSCs. Simultaneously, TLR4 signaling downregulates Bambi expression through MyD88 and NF-κB in HSCs. HSCs become free from restricted TGF-β signaling by the downregulation of Bambi, which eventually induces HSC activation.

Figure 2

Ablation of TAK1 in hepatocytes induces spontaneous liver injury, inflammation, fibrosis, and cancer. Spontaneous hepatocyte death occurs in hepatocyte specific TAK1-deficient mice followed by the release of damage-associated molecular patterns (DAMPs) which stimulate Kupffer cells to produce TNF-α. This TNF-α further induces cell death in TAK1-deficient hepatocytes lacking activation of NF-κB and JNK. TNF-α, IL-1β, and IL-6 released from Kupffer cells cause liver inflammation. Kupffer cell-derived TGF-β stimulates hepatic stellate cells resulting in fibrogenesis. The persistent hepatocyte death and uncontrolled compensatory proliferation in the livers of hepatocyte specific TAK1-deficient mice induce the reactivation of onco-fetal liver genes that are associated with the initiation of hepatic carcinogenesis.