Cholesterol accumulation on dendritic cells reverses chronic hepatitis B virus infection-induced dysfunction,Cellular & Molecular Immunology

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Cholesterol accumulation on dendritic cells reverses chronic hepatitis B virus infection-induced dysfunction
Cellular & Molecular Immunology ( IF 21.8 ) Pub Date : 2022-11-11 , DOI: 10.1038/s41423-022-00939-1
Huajun Zhao ₁ , Yating Yu ₁ , Yucan Wang ₁ , Lianhui Zhao ₂ , Ailu Yang ₁ , Yifei Hu ₁ , Zhaoyi Pan ₁ , Zixuan Wang ₁ , Jiarui Yang ₁ , Qiuju Han ₁ , Zhigang Tian ₃ , Jian Zhang ₁

Affiliation

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.

中文翻译：

树突状细胞上的胆固醇积累可逆转慢性乙型肝炎病毒感染引起的功能障碍

慢性乙型肝炎（CHB）感染仍然是全球严重的公共卫生问题；然而，胆固醇水平与慢性乙型肝炎之间的关系仍不清楚。我们从健康献血者和慢性乙型肝炎患者中分离出外周血单核细胞，以分析游离胆固醇水平、脂筏形成和胆固醇代谢相关途径。生成乙型肝炎病毒 (HBV) 携带小鼠并用于确认 CHB 背景下树突状细胞 (DC) 中胆固醇代谢和细胞表面脂筏形成的变化。此外，使用重组 HBV 疫苗 (rHBVvac) 与亲脂性他汀类药物联合对 HBV 携带小鼠进行免疫，并评估疫苗针对 HBV 的功效。分析血清样本的 HBsAg、抗 HBs 和丙氨酸转氨酶水平，评估肝脏样本的 HBV DNA 和 RNA 以及 HBcAg。 CHB降低了CHB患者和HBV携带小鼠的DC上的游离胆固醇水平并抑制了脂筏的形成，而亲脂性他汀类药物的施用促进了游离胆固醇的积累并恢复了DC上的脂筏，同时增强了体外和体内的抗原呈递能力。 DC 上的胆固醇积累改善了 rHBVvac 介导的血清 HBV DNA 和肝内 HBV DNA、HBV RNA 和 HBcAg 的消除，促进了 rHBVvac 介导的 HBV 特异性 CD11ahi CD8αlo 细胞的生成和多功能性，诱导针对 HBV 的记忆反应的发展再感染，以及从 HBsAg 到抗 HBs 的血清转换。结果证明了胆固醇水平在慢性乙型肝炎期间 DC 功能障碍中的重要作用，表明增加 DC 上胆固醇积累的策略可能会增强针对 HBV 的治疗性疫苗功效，并支持临床 CHB 治疗的发展。

更新日期：2022-11-11

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