HCV core protein inhibits polarization and activity of both M1 and M2 macrophages through the TLR2 signaling pathway.

Qianqian Zhang,Zhengkun Tu,Hongxiao Song,Xiaolin Guo,Tianyang Li,Ian Nicholas Crispe,Junqi Niu,Haijun Li,Yang Wang,Baorong Chi,Naicui Zhai,Lishan Su,Yang Yang

doi:10.1038/srep36160

Abstract

Hepatitis C virus (HCV) establishes persistent infection in most infected patients, and eventually causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma in some patients. Monocytes and macrophages provide the first line of defense against pathogens, but their roles in HCV infection remains unclear. We have reported that HCV core protein (HCVc) manipulates human blood-derived dendritic cell development. In the present study, we tested whether HCVc affects human blood-derived monocyte differentiating into macrophages. Results showed that HCVc inhibits monocyte differentiation to either M1 or M2 macrophages through TLR2, associated with impaired STATs signaling pathway. Moreover, HCVc inhibits phagocytosis activity of M1 and M2 macrophages, M1 macrophage-induced autologous and allogeneic CD4+ T cell activation, but promotes M2 macrophage-induced autologous and allogeneic CD4+ T cell activation. In conclusion, HCVc inhibits monocyte-derived macrophage polarization via TLR2 signaling, leading to dysfunctions of both M1 and M2 macrophages in chronic HCV infected patients. This may contribute to the mechanism of HCV persistent infection, and suggest that blockade of HCVc might be a novel therapeutic approach to treating HCV infection.

Highlights

Hepatitis C virus (HCV) establishes persistent infection in most infected patients, and eventually causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma in some patients
These results suggest that human peripheral monocytes from chronic HCV infected patients fail to polarize toward M1 and M2 macrophages as strongly as cells from healthy donors
HCV core protein (HCVc) down-regulated the expression of CD163 (499.0 ± 35.0 Vs 243.0 ± 14.2, P = 0.0025, Fig. 3c) and CD206 (1098.0 ± 73.4 Vs 697.7 ± 5.2, P = 0.0056, Fig. 3d) on M2 macrophages, as well as IL-10 production (596.5 ± 35.1 Vs 54.8 ± 15.5, P < 0.0001, Fig. 3f), and Arg-1 mRNA expression level (3.0 ± 0.3 Vs 1.1 ± 0.2, P = 0.0004, Fig. 3h), compared with the medium and β-gal controls. These results indicate that HCVc suppressed both M1 and M2 macrophage polarization, which is consistent with chronic HCV infection

Summary

Introduction

Hepatitis C virus (HCV) establishes persistent infection in most infected patients, and eventually causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma in some patients. Results showed that HCVc inhibits monocyte differentiation to either M1 or M2 macrophages through TLR2, associated with impaired STATs signaling pathway. HCVc inhibits monocytederived macrophage polarization via TLR2 signaling, leading to dysfunctions of both M1 and M2 macrophages in chronic HCV infected patients. This may contribute to the mechanism of HCV persistent infection, and suggest that blockade of HCVc might be a novel therapeutic approach to treating HCV infection. Some studies have reported that HCV induces monocyte differentiation and polarization of macrophages that promote liver fibrogenesis in chronic infection[14]. Our previous study showed that HCVc inhibits monocyte differentiation into dendritic cells (DCs)[21]

Methods

Results

Conclusion