Zhao Shixing, Si Meng, Deng Xianpei, Wang Dengqin, Kong Lingbin, Zhang Qianqian
Department of Intensive Care Unit, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, P.R. China.
Department of Foreign Languages, Jining Medical University, Jining, Shandong 272000, P.R. China.
Exp Ther Med. 2022 Jun 16;24(2):522. doi: 10.3892/etm.2022.11448. eCollection 2022 Aug.
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.
丙型肝炎病毒（HCV）在大多数患者中建立持续感染，最终导致慢性丙型肝炎（CHC）、肝硬化和肝细胞癌。我们之前的研究表明，HCV核心蛋白（HCVc）抑制单核细胞向M1和M2巨噬细胞分化。然而，HCVc是否影响M2巨噬细胞的极化，以及这种影响是否促进慢性病进展仍不清楚。在本研究中，分离、纯化了CHC患者和健康对照（HC）的外周血单个核细胞（PBMC），并将其极化为M2a、M2b和M2c巨噬细胞。分别使用流式细胞术、酶联免疫吸附测定（ELISA）和逆转录-定量聚合酶链反应分析表型表达、细胞因子分泌和基因表达。将HC的单核细胞与HCVc一起培养，以研究HCVc对巨噬细胞极化的影响。CHC组的血浆丙氨酸转氨酶和HCV-RNA水平显著高于对照组，白蛋白水平显著低于对照组（P<0.05）。与HC的单核细胞极化而来的M2a巨噬细胞相比，CHC患者的单核细胞极化而来的M2a巨噬细胞表达较低水平的CD209、白细胞介素-1受体拮抗剂（IL-1RA）和Fizz1。与HC相比，CHC组中M2b巨噬细胞表达较低水平的CD86和肿瘤坏死因子-α（TNF-α），M2c巨噬细胞表达较低水平的CD163、转化生长因子-β（TGF-β）和鞘氨醇激酶1（SPHK1）（P<0.05）。HCVc抑制M2a巨噬细胞中CD209、IL-1RA和Fizz1的表达水平；抑制M2b巨噬细胞中CD86和TNF-α的表达水平；抑制M2c巨噬细胞中CD163、TGF-β和SPHK1的表达水平（P<0.05）。HCVc显著抑制所有亚型的吞噬作用（P<0.05）；然而，抗Toll样受体（TLR）2抗体可恢复这种抑制作用（P<0.05）。总之，HCVc通过TLR2信号通路抑制单核细胞来源的M2a、M2b和M2c亚型分化，导致CHC患者的巨噬细胞吞噬作用降低。这可能导致HCV持续感染，因此表明阻断HCVc可能是治疗HCV感染的一种新的治疗方法。
