Background and Aims: The surface antigen of hepatitis B virus (HBsAg) serves as an important immune-modulatory factor in chronic hepatitis B (CHB). One aspect of such modulation may act through monocytes which are the major antigen presenting cells (APCs) taking up HBsAg. There is evidence for the encapsulation of hepatocellular miRNAs by HBsAg particles, while its pathobiological significance is unclear. Here, we characterized the miRNA profile in CHB patients and probed their association with liver inflammation. Approaches and Results: We collected plasma from treatment-naive CHB patients (n=110) and quantified total/HBsAg-enveloped miRNAs by qRT-PCR and plasma cytokines by ELISA. The biological effects of HBsAg-delivered miRNAs in monocytes were evaluated by multiple approaches. The clinical significance of candidate miRNAs and cytokines was corroborated in patients with HBV-associated advanced liver diseases. The plasma miRNA profile showed two major clusters, one significantly associated with HBsAg titer and the other correlated with liver inflammation. Among HBsAg-carried miRNAs, miR-939 displayed most significant correlation with IL-8. Mechanistically, miR-939 in subviral particles enters monocytes and significantly augments IL-8 production via the MAPK p38 signaling pathway. Finally, the findings that miR-939 positively correlated with IL-8 level and inflammation/fibrosis stage in the cohort of HBV-associated advanced liver diseases support its causative role in the progression of liver diseases. Conclusion: HBsAg particles carry hepatocellular miRNAs, including miR-939, which enter monocytes and alter their functional status such as IL-8 secretion. Our findings demonstrate that HBsAg-miR-939-IL-8 axis may play a crucial role in HBV-induced hepatic necro-inflammation and progression of advanced liver diseases.

中文翻译：

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通过乙型肝炎病毒表面抗原颗粒传递肝细胞 MicroRNA 来调节单核细胞活性：对慢性乙型肝炎病理学的影响


背景和目的：乙型肝炎病毒表面抗原（HBsAg）是慢性乙型肝炎（CHB）的重要免疫调节因子。这种调节的一方面可以通过单核细胞发挥作用，单核细胞是吸收 HBsAg 的主要抗原呈递细胞 (APC)。有证据表明 HBsAg 颗粒封装肝细胞 miRNA，但其病理生物学意义尚不清楚。在这里，我们对慢性乙型肝炎患者的 miRNA 谱进行了表征，并探讨了它们与肝脏炎症的关系。方法和结果：我们收集了初治 CHB 患者 (n=110) 的血浆，并通过 qRT-PCR 定量总/HBsAg 包膜的 miRNA，并通过 ELISA 定量血浆细胞因子。通过多种方法评估了单核细胞中 HBsAg 传递的 miRNA 的生物学效应。候选 miRNA 和细胞因子的临床意义在 HBV 相关晚期肝病患者中得到证实。血浆 miRNA 谱显示出两个主要簇，一个与 HBsAg 滴度显着相关，另一个与肝脏炎症相关。在 HBsAg 携带的 miRNA 中，miR-939 与 IL-8 的相关性最显着。从机制上讲，亚病毒颗粒中的 miR-939 进入单核细胞，并通过 MAPK p38 信号通路显着增加 IL-8 的产生。最后，在 HBV 相关晚期肝病队列中 miR-939 与 IL-8 水平和炎症/纤维化阶段呈正相关的研究结果支持其在肝病进展中的致病作用。结论：HBsAg 颗粒携带肝细胞 miRNA，包括 miR-939，其进入单核细胞并改变其功能状态，例如 IL-8 分泌。 我们的研究结果表明，HBsAg-miR-939-IL-8 轴可能在 HBV 诱导的肝脏坏死炎症和晚期肝病进展中发挥至关重要的作用。