Abstract
Mice with different genetic backgrounds have various susceptibilities to infection with Clonorchis sinensis, although the mechanisms underlying are largely unknown. Toll-like receptor 4 (TLR4) as one of the most important pattern recognition receptors (PPRs) is essential for the invasion, survival, pathogenesis, and elimination of worms. The roles played by TLR4 in C. sinensis infection may vary due to the different genetic backgrounds of mice. In the present study, a relatively resistant mouse strain-C57BL/10 to C. sinensis was used for investigation on the possible roles of TLR4 in the biliary injuries and peribiliary fibrosis. TLR4 wild type (TLR4wild) and TLR4 defective (TLR4def) mice were orally infected with 45 metacercariae of C. sinensis, and all C. sinensis-infected mice and non-infected groups were anesthetized on day 28 post-infection. The liver and serum from each mouse were collected for assessment of the biliary injuries and biliary fibrosis. Meanwhile, hepatic leukocytes were isolated and detected for the activation of M1 or M2 macrophage using flow cytometry. The hepatic type 1 immune response and type 2 immune responses -relative molecules were also evaluated using ELISA and quantitative PCR. The data showed that TLR4def aggravated liver inflammatory cell infiltrations, bile duct proliferation, biliary and hepatocellular injuries, and ECM deposition in C. sinensis-infected mice, compared with TLR4wild mice when they were intragastrically administered with the same amounts of C. sinensis metacercaria. Furthermore, the M2-like macrophages and type 2 immune responses were significantly predominant induced in TLR4def mice, compared with that of TLR4wild mice following C. sinensis infection. But the type 1 immune response were significantly decreased in TLR4def mice, compared with TLR4wild mice after C. sinensis infection. These data demonstrate that TLR4 deficiency exacerbates biliary injuries and peribiliary fibrosis caused by C. sinensis in C57BL/10 strain mice, which is contributed by augments of type 2 immune responses and decrease pro-inflammatory responses.
Highlights
Clonorchis sinensis is a zoonotic food-borne parasite which infects human or other mammals via ingestion of raw or undercooked fresh fish and shrimp containing metacercaria (Tang et al, 2016)
TLR4 defective (TLR4def) infected mice had very serious liver damage: a large number of inflammatory cells were infiltrated around the bile duct, the bile duct epithelium was disrupted, the hepatic lobule structure was damaged, and the liver cells were arranged in disorder (Figure 1B, as indicated by arrows)
Mild fibrosis lesions indicating by Masson staining and hydroxyproline assay were found in C. sinensis-infected C57BL/10 and C57BL/6, which further suggested that the susceptibility of different strains of mice to C. sinensis was different (Robey et al, 2015)
Summary
Clonorchis sinensis is a zoonotic food-borne parasite which infects human or other mammals via ingestion of raw or undercooked fresh fish and shrimp containing metacercaria (Tang et al, 2016). Toll-like receptors (TLRs) are an important family of pattern recognition receptors (PRRs), which play a very important role in the innate immune response as well as adaptive immune responses (Akira et al, 2001). It is widely expressed in immune cells (such as macrophages, dendritic cells, NK cells, lymphocytes, granulocytes) and non-immune cells (such as epithelial cells, endothelial cells, fibroblasts, cancer cells, etc.), and is involved in almost all human disease processes (Ciferska et al, 2020). Studies have confirmed that TLR4 plays an important role in liver injury (Cengiz et al, 2015; Seki and Schwabe, 2015; Gandhi, 2020)
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