Abstract
Hepatitis C virus (HCV) establishes a persistent infection in most patients, eventually leading to chronic hepatitis C (CHC), cirrhosis and hepatocellular carcinoma. Our previous study revealed that HCV core protein (HCVc) inhibited the differentiation of monocytes into M1 and M2 macrophages. However, it remains unclear as to whether HCVc affects the polarization of M2 macrophages, and if this effect promotes the progression of chronic disease. In the present study, peripheral blood mononuclear cells (PBMCs) from patients with CHC and healthy controls (HCs) were isolated, purified and polarized to M2a, M2b and M2c macrophages. Phenotypic expression, cytokine secretion and gene expression were analyzed using flow cytometry, ELISA and reverse transcription-quantitative polymerase chain reaction, respectively. Monocytes from HCs were cultured with HCVc to study the effect of HCVc on macrophage polarization. Plasma alanine transaminase and HCV-RNA levels were significantly higher, and albumin levels were significantly lower in the CHC group than those in the control group (P<0.05). M2a macrophages polarized from monocytes of patients with CHC expressed lower levels of CD209, IL-1 receptor antagonist (IL-1RA) and Fizz1 compared with those from HCs. M2b macrophages expressed lower levels of CD86 and TNF-α, and M2c macrophages expressed lower levels of CD163, TGF-β and sphingosine kinase 1 (SPHK1) in the CHC group compared with HCs (P<0.05). HCVc inhibited the expression levels of CD209, IL-1RA and Fizz1 in M2a macrophages; CD86 and TNF-α in M2b macrophages; and CD163, TGF-β and SPHK1 in M2c macrophages (P<0.05). HCVc significantly suppressed phagocytosis of all subtypes (P<0.05); however, this inhibition was restored by an anti-Toll-like receptor (TLR)2 antibody (P<0.05). In conclusion, HCVc inhibited monocyte-derived M2a, M2b and M2c subtype differentiation via the TLR2 signaling pathway, resulting in macrophages exhibiting reduced phagocytosis in patients with CHC. This may contribute to persistent HCV infection, thus suggesting that the blockade of HCVc may be a new therapeutic approach for the treatment of HCV infection.