Up-regulation of A20/ABIN1 contributes to inefficient M1 macrophage polarization during Hepatitis C virus infection

Anti-hepatitis C virus (HCV) responses are often accompanied by an increase in alanine aminotransferase levels in HCV-infected patients, indicating that inflammatory responses are compromised by the virus. Additionally, inflammation is associated with M1-polarizated macrophages, which secrete cytokines such as tumor necrosis factor-α, interleukin-1, and interleukin-12, and present antigens through phagocytosis. HCV-encoded proteins are presented as specific viral antigens in particular infectious steps that influence the immune response. For instance, HCV antigens impact macrophage PD-1 and Tim-3 expression, and contribute to impaired viral clearance. Furthermore, circulatory HCV antigens from infected patients inhibit dendritic cell differentiation, which raises the possibility that HCV antigens may also interfere with macrophage polarization.

In this study, the impact of HCV antigen stimulation on M1-polarized macrophages was investigated. The influence of HCV antigens was evaluated by reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Specific changes were investigated clinically by flow cytometry and immunofluorescence. Effects of NF-κB during the process were analyzed by western blot.

HCV infection dampened M1 macrophage polarization ex vivo and in vitro. After antigen stimulation, NF-κB signaling was suppressed by the up-regulation of A20 and A20-binding inhibitor of NF-κB binding protein, which likely leads to a variation of functional molecules such as tumor necrosis factor-α, CD163, matrix metalloproteinases, transferrin receptor-1, and CD100, reflecting an anti-inflammatory reaction against M1-polarization.

HCV antigens stimulation up-regulates A20/A20-binding inhibitor of NF-κB binding protein expression, which consequently contributes to inefficient M1 macrophage polarization.