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STING signaling activation inhibits HBV replication and attenuates the severity of liver injury and HBV-induced fibrosis

Cellular & Molecular Immunology volume 19, pages 92–107 (2022)Cite this article

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Abstract

The covalently closed circular DNA (cccDNA) of HBV plays a crucial role in viral persistence and is also a risk factor for developing HBV-induced diseases, including liver fibrosis. Stimulator of interferon genes (STING), a master regulator of DNA-mediated innate immune activation, is a potential therapeutic target for viral infection and virus-related diseases. In this study, agonist-induced STING signaling activation in macrophages was revealed to inhibit cccDNA-mediated transcription and HBV replication via epigenetic modification in hepatocytes. Notably, STING activation could efficiently attenuate the severity of liver injury and fibrosis in a chronic recombinant cccDNA (rcccDNA) mouse model, which is a proven suitable research platform for HBV-induced fibrosis. Mechanistically, STING-activated autophagic flux could suppress macrophage inflammasome activation, leading to the amelioration of liver injury and HBV-induced fibrosis. Overall, the activation of STING signaling could inhibit HBV replication through epigenetic suppression of cccDNA and alleviate HBV-induced liver fibrosis through the suppression of macrophage inflammasome activation by activating autophagic flux in a chronic HBV mouse model. This study suggests that targeting the STING signaling pathway may be an important therapeutic strategy to protect against persistent HBV replication and HBV-induced fibrosis.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (C31872731, C32070910, C31470839) and Zhengyi Scholar Foundation of School of Basic Medical Sciences, Fudan University (S25-01).

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  1. These authors contributed equally: Yuqi Li, Minjing He, Ziyu Wang.

Authors and Affiliations

  1. Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032, China

    Yuqi Li, Minjing He, Ziyu Wang, Zhiyun Duan, Zhiwei Guo, Ziteng Wang, Ruijie Gong, Tianhao Chu & Bo Gao

  2. Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Jiabin Cai

  3. Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University & Ministry of Education, Shanghai, 200032, China

    Jiabin Cai

  4. Key Laboratory of Medical Epigenetics and Metabolism, Institute of Biomedical Sciences, Fudan University, Shanghai, 200032, China

    Jiabin Cai

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BG and JBC conceived and supervised the study. BG, JBC, YQL, MJH, and ZYW participated in the study design and analyzed the data. YQL, MJH, ZYW, ZYD, ZWG ZTW, RJG, and THC performed the experiments. BG, YQL, and MJH wrote the manuscript.

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Correspondence to Jiabin Cai or Bo Gao.

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Li, Y., He, M., Wang, Z. et al. STING signaling activation inhibits HBV replication and attenuates the severity of liver injury and HBV-induced fibrosis. Cell Mol Immunol 19, 92–107 (2022). https://doi.org/10.1038/s41423-021-00801-w

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