Ganesan Murali, Pathania Anup S, Bybee Grace, Kharbanda Kusum K, Poluektova Larisa Y, Osna Natalia A
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA.
Biomolecules. 2025 Jan 3;15(1):57. doi: 10.3390/biom15010057.
About 296 million people worldwide are living with chronic hepatitis B viral (HBV) infection, and outcomes to end-stage liver diseases are potentiated by alcohol. HBV replicates in hepatocytes, but other liver non-parenchymal cells can sense the virus. In this study, we aimed to investigate the regulatory effects of macrophages on HBV marker and interferon-stimulated genes (ISGs) expressions in hepatocytes. This study was performed on HBV-replicating HepG2.2.15 cells and human monocyte-derived macrophages (MDMs). We found that exposure of HepG2.2.15 cells to an acetaldehyde-generating system (AGS) increased HBV RNA, HBV DNA, and cccDNA expressions and suppressed the activation of ISGs, , , and . Supernatants collected from IFNα-activated MDMs decreased HBV marker levels and induced ISG activation in AGS-treated and untreated HepG2.215 cells. These effects were reversed by exposure of MDMs to ethanol and mimicked by treatment with exosome release inhibitor GW4869. We conclude that exosome-mediated crosstalk between IFN-activated macrophages and HBV-replicating hepatocytes plays a protective role via the up-regulation of ISGs and suppression of HBV replication. However, ethanol exposure to macrophages breaks this protection.
全球约有2.96亿人感染慢性乙型肝炎病毒（HBV），而酒精会加剧发展为终末期肝病的后果。HBV在肝细胞中复制，但其他肝脏非实质细胞也能感知到该病毒。在本研究中，我们旨在探究巨噬细胞对肝细胞中HBV标志物和干扰素刺激基因（ISG）表达的调节作用。本研究使用了复制HBV的HepG2.2.15细胞和人单核细胞衍生巨噬细胞（MDM）。我们发现，将HepG2.2.15细胞暴露于乙醛生成系统（AGS）会增加HBV RNA、HBV DNA和cccDNA的表达，并抑制ISG（ 、 、 和 ）的激活。从IFNα激活的MDM收集的上清液可降低AGS处理和未处理的HepG2.215细胞中的HBV标志物水平，并诱导ISG激活。MDM暴露于乙醇后，这些作用会逆转，而用外泌体释放抑制剂GW4869处理可模拟这些作用。我们得出结论，IFN激活的巨噬细胞与复制HBV的肝细胞之间通过外泌体介导的相互作用，通过上调ISG和抑制HBV复制发挥保护作用。然而，巨噬细胞暴露于乙醇会破坏这种保护作用。
