TY - JOUR
T1 - Modulation of monocyte activity by hepatocellular MicroRNA delivery through HBsAg particles
T2 - Implications for pathobiology of chronic hepatitis B
AU - Li, Jin
AU - Ma, Xiao
AU - Xuan, Qinkao
AU - Li, Qiang
AU - Wu, Min
AU - Shi, Bisheng
AU - Fang, Zhong
AU - Chen, Liang
AU - Chen, Jieliang
AU - Wen, Yumei
AU - Zhu, Chuanwu
AU - Zhu, Li
AU - Zhang, Xiaonan
AU - Yuan, Zhenghong
N1 - Funding Information:
This study was supported by grants from the National Key R&D Program of China (2021YFC2300600, 2022YFA1303600, 2023YFC2308603), the National Natural Science Foundation of China (U23A20474, 81902054, 82172252), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2023-PT310-02), the Shanghai Municipal Science and Technology Major Project (ZD2021CY001), the Natural Science Foundation of Jiangsu Province (BK20211080), the Social Development Program of Jiangsu Province (BE2022734) and the Science and Technology Project of Suzhou (SKY2022061, SKY2023221).
Publisher Copyright:
© 2024 Lippincott Williams and Wilkins. All rights reserved.
PY - 2024/6
Y1 - 2024/6
N2 - Background and Aims: HBsAg serves as an important immune-modulatory factor in chronic hepatitis B. One aspect of such modulation may act through monocytes, which are the major Ag-presenting cells taking up HBsAg. There is evidence for the encapsulation of hepatocellular microRNAs (miRNAs) by HBsAg particles, while its pathobiological significance is unclear. Here, we characterized the miRNA profile in patients with chronic hepatitis B and probed their association with liver inflammation. Approaches and Results: We collected plasma from patients that are treatment-naive with chronic hepatitis B (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 using 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 2 major clusters, one significantly associated with HBsAg titer and the other correlated with liver inflammation. Among HBsAg-carried miRNAs, miR-939 displayed the most significant correlation with IL-8. Mechanistically, miR-939 in subviral particles enters monocytes and significantly augments IL-8 production through the mitogen-activated protein kinase (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. Conclusions: 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 the HBsAg-miR-939-IL-8 axis may play a crucial role in HBV-induced hepatic necro-inflammation and the progression of advanced liver diseases.
AB - Background and Aims: HBsAg serves as an important immune-modulatory factor in chronic hepatitis B. One aspect of such modulation may act through monocytes, which are the major Ag-presenting cells taking up HBsAg. There is evidence for the encapsulation of hepatocellular microRNAs (miRNAs) by HBsAg particles, while its pathobiological significance is unclear. Here, we characterized the miRNA profile in patients with chronic hepatitis B and probed their association with liver inflammation. Approaches and Results: We collected plasma from patients that are treatment-naive with chronic hepatitis B (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 using 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 2 major clusters, one significantly associated with HBsAg titer and the other correlated with liver inflammation. Among HBsAg-carried miRNAs, miR-939 displayed the most significant correlation with IL-8. Mechanistically, miR-939 in subviral particles enters monocytes and significantly augments IL-8 production through the mitogen-activated protein kinase (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. Conclusions: 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 the HBsAg-miR-939-IL-8 axis may play a crucial role in HBV-induced hepatic necro-inflammation and the progression of advanced liver diseases.
UR - http://www.scopus.com/inward/record.url?scp=85198989367&partnerID=8YFLogxK
U2 - 10.1097/HEP.0000000000000972
DO - 10.1097/HEP.0000000000000972
M3 - Article
C2 - 38904485
AN - SCOPUS:85198989367
SN - 0270-9139
SP - 1
EP - 17
JO - Hepatology
JF - Hepatology
ER -
