Abstract
Although several evidences suggesting the vital roles that innate immunity plays in the persistence and elimination of chronic hepatitis B virus (CHB) infection, the exact mechanism is still complicated. Here, we successfully polarized monocytes derived from healthy human peripheral blood mononuclear cells (PBMCs) into M1/M2 macrophages and detected the effects of hepatitis B core antigen (HBcAg) on the polarization and function of macrophages via the Toll-like receptor (TLR) 2 signaling pathway. The results showed that HBcAg had a negligible impact on M1 polarization, while it effectively impaired M2 polarization and promoted the production of pro-inflammatory cytokines such as IL-6 and TNF-α. Additionally, HBcAg treatment increased TLR2 expression on M2 macrophages and TLR2 blockade abolished the effects of HBcAg on the impaired phenotype and pro-inflammatory cytokine productions of M2 macrophages. Signaling pathway analysis revealed that the nuclear factor κB (NF-κB) pathway, the downstream of TLR2, was upregulated upon HBcAg treatment in both M1 and M2 macrophages. Furthermore, a CD8+ T-macrophage coculture system implied that compared with PBS stimulation, HBcAg-stimulated M2 macrophages regained their ability to activate CD8+ T cells with higher secretion of IFN-γ. Finally, we found impaired expression of M2-related molecules and increased levels of pro-inflammation cytokines in M2 macrophages from CHB patients upon HBcAg stimulation. In conclusion, these results imply a favorable role of HBcAg in the establishment of a pro-inflammatory microenvironment by macrophages, which may suggest a potential therapeutic strategy of HBcAg-induced macrophage activation in CHB infection.
Highlights
Hepatitis B virus (HBV) infection remains a heavy public health burden that still affects ∼250 million people around the world, despite the effective use of HBV vaccination [1]
As previous studies revealed [15], we found that M1 MΦ expressed more costimulatory molecules such as CD40 and CD80 than M2 MΦ, while macrophage mannose receptor (MMR), namely CD206, and CD163 were both upregulated in M2 MΦ compared with M1 MΦ (Figures 1B–D)
In the current study, using monocyte-derived macrophages obtained from healthy individuals or chronic hepatitis B virus (CHB) patients, we determined the effects of hepatitis B core antigen (HBcAg) on macrophage polarization and further assessed the involvement of the TLR2 signaling pathway
Summary
Hepatitis B virus (HBV) infection remains a heavy public health burden that still affects ∼250 million people around the world, despite the effective use of HBV vaccination [1]. There are two main branches of liver macrophages: the cells in the largest branch are termed Kupffer cells (KCs), and those in the other are defined as monocyte-derived infiltrating macrophages. Liver diseases such as infection or injury may trigger KC activation, inducing the secretion of pro-inflammatory cytokines to defend pathogens, and may even produce inhibitory cytokines to support liver remodeling and immune tolerance. The antiviral effects of liver monocytederived infiltrating macrophages on the process of HBV infection are still unresolved.
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