RT Journal Article
SR Electronic
T1 miR-146a Maintains Immune Tolerance of Kupffer Cells and Facilitates Hepatitis B Virus Persistence in Mice
JF The Journal of Immunology
JO J. Immunol.
FD American Association of Immunologists
SP 2558
OP 2572
DO 10.4049/jimmunol.2100618
VO 208
IS 11
A1 Liu, Yongai
A1 Qin, Lijuan
A1 Wang, Jiuru
A1 Xie, Xialin
A1 Zhang, Yu
A1 Li, Changfei
A1 Guan, Zeliang
A1 Qian, Liyuan
A1 Chen, Lizhao
A1 Hu, Jun
A1 Meng, Songdong
YR 2022
UL http://www.jimmunol.org/content/208/11/2558.abstract
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.