Ly6C+ Monocytes and Kupffer Cells Orchestrate Liver Immune Responses Against Hepatitis B Virus in Mice

Abstract

To understand the mechanism(s) of age‐dependent outcomes of HBV infection in humans, we previously established an age‐related HBV mouse model in which six‐week‐old (N6W) C3H/HeN exhibited virus tolerance, while 12‐week‐old (N12W) counterparts represented 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 (HDI). Serum HBV markers were monitored weekly. Hepatic leucocyte populations and their cytokine/chemokine productions were examined at baseline, day 3 (D3), D7, and D14 post injection. CCR2 antagonist and clodronate were respectively, administrated to N12W and N6W mice, to study the roles of Ly6C⁺ monocytes and kupffer cells (KCs) in viral clearance. Twelve‐week‐old 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 IFNγ⁺TNFα⁺CD8⁺ T cells at D7 was only seen in the older cohort. The enhanced Ly6C⁺ monocyte induction in N12W resulted from elevated CCL2 secretion by hepatocytes. CCR2 antagonist administration hampered Ly6C⁺ monocyte recruitment and degree of KC reduction, and delayed HBV clearance in 12‐week‐old animals. Depletion of KCs by clodronate liposomes enhanced Ly6C⁺ monocyte recruitment and accelerated HBV clearance in six‐week‐old 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.

This article is protected by copyright. All rights reserved.

http://bit.ly/2T5tJYz