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Cholesterol accumulation on dendritic cells reverses chronic hepatitis B virus infection-induced dysfunction

Cellular & Molecular Immunology volume 19, pages 1347–1360 (2022)Cite this article

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Abstract

Chronic hepatitis B (CHB) infection remains a serious public health problem worldwide; however, the relationship between cholesterol levels and CHB remains unclear. We isolated peripheral blood mononuclear cells from healthy blood donors and CHB patients to analyze free cholesterol levels, lipid raft formation, and cholesterol metabolism-related pathways. Hepatitis B virus (HBV)-carrier mice were generated and used to confirm changes in cholesterol metabolism and cell-surface lipid raft formation in dendritic cells (DCs) in the context of CHB. Additionally, HBV-carrier mice were immunized with a recombinant HBV vaccine (rHBVvac) combined with lipophilic statins and evaluated for vaccine efficacy against HBV. Serum samples were analyzed for HBsAg, anti-HBs, and alanine aminotransferase levels, and liver samples were evaluated for HBV DNA and RNA and HBcAg. CHB reduced free cholesterol levels and suppressed lipid raft formation on DCs in patients with CHB and HBV-carrier mice, whereas administration of lipophilic statins promoted free cholesterol accumulation and restored lipid rafts on DCs accompanied by an enhanced antigen-presentation ability in vitro and in vivo. Cholesterol accumulation on DCs improved the rHBVvac-mediated elimination of serum HBV DNA and intrahepatic HBV DNA, HBV RNA, and HBcAg and promoted the rHBVvac-mediated generation and polyfunctionality of HBV-specific CD11ahi CD8αlo cells, induction of the development of memory responses against HBV reinfection, and seroconversion from HBsAg to anti-HBs. The results demonstrated the important role of cholesterol levels in DC dysfunction during CHB, suggesting that strategies to increase cholesterol accumulation on DCs might enhance therapeutic vaccine efficacy against HBV and support development toward clinical CHB treatment.

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Acknowledgements

This work was supported by the National Key Research and Development Programme (2021YFC2300603), the National Postdoctoral Programme for Innovative Talents (No. BX20190192), the China Postdoctoral Science Foundation (No. 2020M672064), and the National Science Foundation for Young Scientists of China (No. 82001687). We thank the Pharmaceutical Biology Sharing Platform of Shandong University and the Translational Medicine Core Facility of Shandong University for consultation and instrument availability supporting this work.

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Authors and Affiliations

  1. Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, 250012, China

    Huajun Zhao, Yating Yu, Yucan Wang, Ailu Yang, Yifei Hu, Zhaoyi Pan, Zixuan Wang, Jiarui Yang, Qiuju Han & Jian Zhang

  2. Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China

    Lianhui Zhao

  3. School of Life Sciences, University of Science and Technology of China, Hefei, 230000, China

    Zhigang Tian

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Contributions

JZ, ZGT, and HJZ conceived and designed the experiments; HJZ, YTY, YCW, LHZ, and ALY performed the experiments; HJZ, YFH, ZYP, ZXW, JRY, and QJH analyzed the data; JZ and HJZ wrote the manuscript, and all authors critically read and approved the final manuscript.

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Correspondence to Jian Zhang.

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Zhao, H., Yu, Y., Wang, Y. et al. Cholesterol accumulation on dendritic cells reverses chronic hepatitis B virus infection-induced dysfunction. Cell Mol Immunol 19, 1347–1360 (2022). https://doi.org/10.1038/s41423-022-00939-1

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