Li Jiahui, Yu Mengxue, Zong Ruobin, Fan Chengpeng, Ren Fu, Wu Wei, Li Changyong
Department of Anatomy and Histology Embryology, Jinzhou Medical University, Jinzhou, People's Republic of China.
Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, People's Republic of China.
Am J Physiol Gastrointest Liver Physiol. 2022 Apr 1;322(4):G459-G471. doi: 10.1152/ajpgi.00338.2021. Epub 2022 Mar 2.
Hepatic macrophages are involved in both pathogen clearance and immunopathogenesis. Emerging evidence demonstrates that macrophage polarization plays a critical role in hepatitis B virus (HBV)-induced immune impairment and liver pathology. However, it remains largely unknown as to how HBV infection facilitates M2 macrophage polarization. Here, a mouse HBV infection model was established by hydrodynamic injection with a vector containing 1.3-fold overlength HBV genome via the tail vein. Coculture experiments with HBV-producing HepG2.2.15 cells and macrophages were established in vitro. We found that HBV-inhibited M1 while enhancing M2 markers, which was accompanied by decreased proinflammatory tumor necrosis factor-α (TNF-α) and augmented anti-inflammatory IL-10 expression. Furthermore, both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) secretion contributed to HBV-triggered macrophage polarization from M1 toward M2 phenotype. Mechanistically, HBsAg and HBeAg could upregulate the sirtuins 1 (SIRT1) deacetylase expression, which in turn promote deacetylation of the Notch1 intracellular domain (NICD), leading to increased Akt phosphorylation and decreased NF-κB nuclear translocation in macrophages. Our findings suggest that NICD deacetylation by SIRT1 contributes to HBsAg- and HBeAg-mediated M2 macrophage polarization, raising the possibility of targeting SIRT1/Notch1 pathway in macrophages to treat HBV immune evasion and chronic HBV infection. This study identified a previously unrecognized molecular mechanism of HBV-mediated suppression of innate immune responses. We demonstrate that deacetylation of NICD by SIRT1 contributes to HBsAg- and HBeAg-mediated M2 macrophage polarization, which may aid in the development of new macrophage-based immunotherapy for chronic HBV infection and related diseases.
肝巨噬细胞参与病原体清除和免疫发病机制。新出现的证据表明，巨噬细胞极化在乙型肝炎病毒（HBV）诱导的免疫损伤和肝脏病理中起关键作用。然而，HBV感染如何促进M2巨噬细胞极化在很大程度上仍不清楚。在此，通过尾静脉水动力注射含1.3倍超长HBV基因组的载体建立了小鼠HBV感染模型。在体外建立了产生HBV的HepG2.2.15细胞与巨噬细胞的共培养实验。我们发现，HBV抑制M1标志物而增强M2标志物，同时促炎肿瘤坏死因子-α（TNF-α）表达降低，抗炎性白细胞介素-10表达增加。此外，乙肝表面抗原（HBsAg）和乙肝e抗原（HBeAg）的分泌均有助于HBV触发巨噬细胞从M1向M2表型极化。机制上，HBsAg和HBeAg可上调沉默调节蛋白1（SIRT1）去乙酰化酶表达，进而促进Notch1胞内结构域（NICD）的去乙酰化，导致巨噬细胞中Akt磷酸化增加和NF-κB核转位减少。我们的研究结果表明，SIRT1介导的NICD去乙酰化有助于HBsAg和HBeAg介导的M2巨噬细胞极化，这增加了靶向巨噬细胞中SIRT1/Notch1通路治疗HBV免疫逃逸和慢性HBV感染的可能性。本研究确定了一种此前未被认识的HBV介导的先天性免疫反应抑制分子机制。我们证明，SIRT1介导的NICD去乙酰化有助于HBsAg和HBeAg介导的M2巨噬细胞极化，这可能有助于开发针对慢性HBV感染及相关疾病的新型巨噬细胞免疫疗法。
