Lymphocyte Antigen 6 Complex, Locus C+ Monocytes and Kupffer Cells Orchestrate Liver Immune Responses Against Hepatitis B Virus in Mice

Autor: Li Ling Wu, Hurng-Yi Wang, Yan Rong Chen, Yen Tien Hong, Hui Lin Wu, Shi-Chuen Miaw, Pei Hsuan Liao, Shiou-Hwei Yeh, Jing Shan Lin, Pei-Jer Chen, Hung-Chih Yang, Ding-Shinn Chen, Wei Hao Peng
Rok vydání: 2019
Předmět:
Zdroj: Hepatology. 69:2364-2380
ISSN: 1527-3350
0270-9139
DOI: 10.1002/hep.30510
Popis: To understand the mechanism(s) of age-dependent outcomes of hepatitis B virus (HBV) infection in humans, we previously established an age-related HBV mouse model in which 6-week-old (N6W) C3H/HeN mice exhibited virus tolerance whereas 12-week-old (N12W) counterparts presented virus clearance. By investigating the hepatic myeloid cell dynamics in mice of these two ages, we aim to identify factors associated with HBV clearance. C3H/HeN mice were transfected with an HBV plasmid by hydrodynamic injection. Serum HBV markers were monitored weekly. Hepatic leucocyte populations and their cytokine/chemokine productions were examined at baseline, day 3 (D3), day 7 (D7), and day 14 after injection. C-C chemokine receptor type 2 (CCR2) antagonist and clodronate (CLD) were respectively administered to N12W and N6W mice to study the roles of lymphocyte antigen 6 complex, locus C (Ly6C)+ monocytes and Kupffer cells (KCs) in viral clearance. N12W mice had a significantly higher number of TNF-α-secreting Ly6C+ monocytes and fewer IL-10-secreting KCs at D3 in the liver than their younger N6W counterparts after HBV transfection. In addition, the elevated number of interferon-γ+ TNF-α+ CD8+ T cells at D7 was only seen in the older cohort. The enhanced Ly6C+ monocyte induction in N12W mice resulted from elevated C-C motif chemokine ligand 2 (CCL2) secretion by hepatocytes. CCR2 antagonist administration hampered Ly6C+ monocyte recruitment and degree of KC reduction and delayed HBV clearance in N12W animals. Depletion of KCs by CLD liposomes enhanced Ly6C+ monocyte recruitment and accelerated HBV clearance in N6W mice. Conclusions: Ly6C+ monocytes and KCs may, respectively, represent the resistance and tolerance arms of host defenses. These two cell types play an essential role in determining HBV clearance/tolerance. Manipulation of these cells is a promising avenue for immunotherapy of HBV-related liver diseases.
Databáze: OpenAIRE
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