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TLR3 activation by Clonorchis sinensis infection alleviates the fluke-induced liver fibrosis
Yuru Wang1, Pengtao Gong1, Xuancheng Zhang1
1State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China.
Abstract:
Clonorchis sinensis is a zoonotic parasite associated with liver fibrosis and cholangiocarcinoma development. The role of toll-like receptors (TLRs) in C. sinensis infection has not yet been fully elucidated. Here, the TLR3 signaling pathway, cytokine expression and liver fibrosis were examined in C. sinensis-infected wildtype (WT) and TLR3-/- mice. Polyinosinic-polycytidylic acid (Poly (I:C)) was used to treat C. sinensis infections. The results showed that TLR3 deficiency caused severe clonorchiasis with increased parasite burden, exacerbated proinflammatory cytokine expression and liver lesions, promoted the TGF-β1/Smad2/3 pathway and myofibroblast activation, exacerbated liver fibrosis (compared to WT mice). Poly (I:C) intervention increased the body weight, decreased mouse mortality and parasite burden, reduced liver inflammation, and alleviated C. sinensis-induced liver fibrosis. Furthermore, C. sinensis extracellular vesicles (CsEVs) promote the production of IL-6, TNF in WT biliary epithelial cells (BECs) via p38/ERK pathway, compared with control group, while TLR3 deletion induced much higher levels of IL-6 and TNF in TLR3-/- BECs than that in WT BECs. Taken together, TLR3 inhibit IL-6 and TNF production via p38/ERK signaling pathway, a phenomenon that resulted in the alleviation of C. sinensis-induced liver fibrosis. Poly (I:C) is a potential treatment for clonorchiasis.
Insights
Toll-like receptor 3 (TLR3) normally inhibits liver inflammation and fibrosis during Clonorchis sinensis infection. Activating TLR3 with Poly(I:C) offers a potential treatment for clonorchiasis, reducing parasite burden and liver damage.
Area of Science:
- Immunology
- Parasitology
- Hepatology
Background:
- Clonorchis sinensis infection is linked to liver fibrosis and cholangiocarcinoma.
- The precise role of toll-like receptors (TLRs), particularly TLR3, in C. sinensis infection remains unclear.
- Understanding TLR3's function is crucial for developing therapeutic strategies against clonorchiasis.
Purpose of the Study:
- To investigate the role of the TLR3 signaling pathway in C. sinensis infection.
- To examine the impact of TLR3 deficiency on cytokine expression and liver fibrosis.
- To evaluate the therapeutic potential of Polyinosinic-polycytidylic acid (Poly(I:C)) in treating C. sinensis infection.
Main Methods:
- Comparison of C. sinensis-infected wildtype (WT) and TLR3-/- mice.
- Administration of Poly(I:C) to infected mice.
- Analysis of cytokine expression, TGF-β1/Smad2/3 pathway activation, and liver fibrosis markers.
- Investigation of C. sinensis extracellular vesicles (CsEVs) effects on biliary epithelial cells (BECs) via p38/ERK pathway.
Main Results:
- TLR3 deficiency exacerbated C. sinensis-induced liver fibrosis, parasite burden, and inflammation.
- Poly(I:C) treatment improved host survival, reduced parasite load, and alleviated liver damage and fibrosis.
- TLR3 deletion enhanced IL-6 and TNF production in BECs, indicating TLR3 normally suppresses these cytokines via the p38/ERK pathway.
Conclusions:
- TLR3 plays a protective role against C. sinensis-induced liver fibrosis by inhibiting IL-6 and TNF production through the p38/ERK pathway.
- Poly(I:C) demonstrates significant therapeutic potential for treating clonorchiasis by mitigating liver inflammation and fibrosis.
