促炎细胞因子
乙型肝炎病毒
免疫学
免疫系统
生物
CTL公司*
人口
获得性免疫系统
免疫
病毒学
病毒
CD8型
医学
炎症
环境卫生
作者
Yongai Liu,Lijuan Qin,Jiuru Wang,Xialin Xie,Yu Zhang,Changfei Li,Zeliang Guan,Qian Liu,Lizhao Chen,Jun Hu,Songdong Meng
出处
期刊:Journal of Immunology
[The American Association of Immunologists]
日期:2022-06-01
卷期号:208 (11): 2558-2572
被引量:2
标识
DOI:10.4049/jimmunol.2100618
摘要
Kupffer cells (KCs), the largest tissue-resident macrophage population in the body, play a central role in maintaining a delicate balance between immune tolerance and immunity in the liver. However, the underlying molecular mechanism remains elusive. In this study, we show that KCs express high levels of miR-146a, which is under control of the PU.1 transcription factor. miR-146a deficiency promoted KCs differentiation toward a proinflammatory phenotype; conversely, miR-146a overexpression suppressed this phenotypic differentiation. We found that hepatitis B virus (HBV) persistence or HBV surface Ag treatment significantly upregulated miR-146a expression and thereby impaired polarization of KCs toward a proinflammatory phenotype. Furthermore, in an HBV carrier mouse model, KCs depletion by clodronate liposomes dramatically promoted HBV clearance and enhanced an HBV-specific hepatic CD8+ T cell and CD4+ T cell response. Consistent with this finding, miR-146a knockout mice cleared HBV faster and elicited a stronger adaptive antiviral immunity than wild-type mice. In vivo IL-12 blockade promoted HBV persistence and tempered the HBV-specific CTL response in the liver of miR-146a knockout mice. Taken together, our results identified miR-146a as a critical intrinsic regulator of an immunosuppressive phenotype in KCs under inflammatory stimuli, which may be beneficial in maintenance of liver homeostasis under physiological condition. Meanwhile, during HBV infection, miR-146a contributed to viral persistence by inhibiting KCs proinflammatory polarization, highlighting its potential as a therapeutic target in HBV infection.
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