Neutrophil depletion exacerbates Clonorchis sinensis associated hepatobiliary injury through expansion of Kupffer cells and Ly6Clo monocytes

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Neutrophils exert diverse functions in parasitic infections, including pathogen clearance and regulation of inflammation. However, their specific roles during the early stage of infection with Clonorchis sinensis , a significant foodborne parasite that dwells in the bile ducts, remain largely unknown. In this study, FVB mice were orally infected with 50 C. sinensis metacercariae, and neutrophils were depleted using an anti-Ly6G antibody; IgG isotype served as the control. Mice were sacrificed 14 days post-infection, and serum and liver tissue were collected to assess hepatobiliary injury. Hepatic leukocyte changes were analyzed by flow cytometry, and associated cytokine/chemokine expression was detected by qPCR. Results showed that neutrophil-depleted mice exhibited significantly aggravated hepatobiliary injury, as evidenced by elevated serum ALT/AST, epithelial hyperplasia, inflammatory infiltration, and ductal dilatation. Neutrophil depletion also exacerbated infection-induced hepatic fibrosis, indicated by increased collagen fiber deposition and increased mRNA levels of Acta2 , Col3a1 and Tgfb1 . Flow cytometry revealed reduced absolute T cell counts but increased CD45 + CD11b lo F4/80 hi Kupffer cells and CD45 + CD11b + Ly6G − Ly6C lo monocytes in neutrophil-depleted infected mice. Additionally, neutrophil depletion increased mRNA levels of Axl , Mertk , Nr4a1 , Cx3cr1 , Cx3cl1 , Tnfα , Il1b , Il10 and Ccl2 , while down-regulating Cxcl1 in infected mice. Collectively, these findings indicate a protective role of neutrophils in early C. sinensis infection in this murine model. Neutrophil depletion induces compensatory expansion of Kupffer cells and Ly6C lo monocytes, forming a pro-inflammatory and pro-fibrotic microenvironment that accelerates liver damage. The results highlight neutrophils as important modulators of hepatic immune responses during clonorchiasis and point to the need for further investigation into neutrophil-mediated regulation of helminth-associated liver pathology.

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