The roles of Toll-like receptor 4 in the pathogenesis of pathogen-associated biliary fibrosis caused by Clonorchis sinensis

Pathogen-associated biliary fibrosis (PABF) is a type of liver fibrosis characterized by injuries of cholangiocytes and extra cellular matrix (ECM) deposition around bile ducts caused by various bacteria, fungi, virus and parasites. Recent studies show that TLR4 plays an important role in several other types of liver fibrosis, but the mechanism of TLR4 in PABF is yet really unclear. In the present study, a PABF mouse model was established by a trematode infection-Clonorchis sinensis which dwells in the bile ducts and causes severe biliary fibrosis of mice. The results showed that the levels of collagen depositions, α-SMA and hydroxyproline (Hyp) contents in TLR4(mut) mice infected by C. sinensis were significantly lower than in those of TLR4(wild) ones. Furthermore, we found that the activation of TGF-β signaling was impaired in the TLR4(mut) mice, compared with wild mice when they were challenged to the same dose of C. sinensis metacercariae. Moreover, the mice with TLR4 mutation showed a decreased activation of hepatic stellate cells indicated by the expression of α-SMA, when compared with TLR4(wild) mice. These data demonstrate that TLR4 contributes to PABF caused by C. sinensis and TLR4 signaling may be a potential medical target for treatment of PABF.