PT  - JOURNAL ARTICLE
AU  - Liu, Yongai
AU  - Qin, Lijuan
AU  - Wang, Jiuru
AU  - Xie, Xialin
AU  - Zhang, Yu
AU  - Li, Changfei
AU  - Guan, Zeliang
AU  - Qian, Liyuan
AU  - Chen, Lizhao
AU  - Hu, Jun
AU  - Meng, Songdong
TI  - miR-146a Maintains Immune Tolerance of Kupffer Cells and Facilitates Hepatitis B Virus Persistence in Mice
AID  - 10.4049/jimmunol.2100618
DP  - 2022 Jun 01
TA  - The Journal of Immunology
PG  - 2558--2572
VI  - 208
IP  - 11
4099  - http://www.jimmunol.org/content/208/11/2558.short
4100  - http://www.jimmunol.org/content/208/11/2558.full
SO  - J. Immunol.2022 Jun 01; 208
AB  - The abundant miR-146a in KCs plays a key role in maintaining immune homeostasis.miR-146a promotes HBV persistence by inhibiting KCs proinflammatory polarization.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.