Ly6C +单核细胞和库普弗细胞协调小鼠对乙型肝炎病毒的肝脏

StephenW

Hepatology. 2019 Jan 19. doi: 10.1002/hep.30510. [Epub ahead of print]
Ly6C+ Monocytes and Kupffer Cells Orchestrate Liver Immune Responses Against Hepatitis B Virus in Mice.
Wu LL1, Peng WH2,3, Wu HL4, Miaw SC5, Yeh SH6, Yang HC6, Liao PH1, Lin JS1, Chen YR1, Hong YT1, Wang HY1,7, Chen PJ1,4,6,8,9, Chen DS1,4,8,9.
Author information

1
    Graduate Institute of Clinical Medicine.
2
    Anatomy and Cell Biology.
3
    School of Medicine for International Students, I-Shou University (Yanchao Campus), Kaohsiung, Taiwan.
4
    Hepatitis Research Center.
5
    Graduate institute of immunology.
6
    Department of Microbiology.
7
    Institute of Ecology and Evolutionary Biology.
8
    Department of Internal Medicine.
9
    Department of Medical Research, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei.

Abstract

To understand the mechanism(s) of age-dependent outcomes of HBV infection in humans, we previously established an age-related HBV mouse model in which six-week-old (N6W) C3H/HeN exhibited virus tolerance, while 12-week-old (N12W) counterparts represented virus clearance. By investigating the hepatic myeloid cell dynamics in mice of these two ages, we aim to identify factors associated with HBV clearance. C3H/HeN mice were transfected with an HBV plasmid by hydrodynamic injection (HDI). Serum HBV markers were monitored weekly. Hepatic leucocyte populations and their cytokine/chemokine productions were examined at baseline, day 3 (D3), D7, and D14 post injection. CCR2 antagonist and clodronate were respectively, administrated to N12W and N6W mice, to study the roles of Ly6C+ monocytes and kupffer cells (KCs) in viral clearance. Twelve-week-old mice had a significantly higher number of TNF-α-secreting Ly6C+ monocytes and fewer IL-10-secreting KCs at D3 in the liver than their younger N6W counterparts after HBV transfection. In addition, the elevated number of IFNγ+ TNFα+ CD8+ T cells at D7 was only seen in the older cohort. The enhanced Ly6C+ monocyte induction in N12W resulted from elevated CCL2 secretion by hepatocytes. CCR2 antagonist administration hampered Ly6C+ monocyte recruitment and degree of KC reduction, and delayed HBV clearance in 12-week-old animals. Depletion of KCs by clodronate liposomes enhanced Ly6C+ monocyte recruitment and accelerated HBV clearance in six-week-old mice. Conclusions.Ly6C+ monocytes and KCs may, respectively, represent the resistance and tolerance arms of host defenses. These two cell types play an essential role in determining HBV clearance/tolerance. Manipulation of these cells is a promising avenue for immunotherapy of HBV-related liver diseases. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.
KEYWORDS:

apoptosis; interferon-γ; macrophage; toll-like receptor 4; tumor necrosis factor-α

PMID:
    30661248
DOI:
    10.1002/hep.30510

StephenW

肝病。 2019年1月19日doi：10.1002 / hep.30510。 [印刷前的电子版]
Ly6C +单核细胞和库普弗细胞协调小鼠对乙型肝炎病毒的肝脏免疫应答。
Wu LL1，Peng WH2,3，Wu HL4，Miaw SC5，Yeh SH6，Yang HC6，Liao PH1，Lin JS1，Chen YR1，Hong YT1，Wang HY1,7，Chen PJ1,4,6,8,9，Chen DS1 ，4,8,9。
作者信息

1
    临床医学研究所。
2
    解剖学和细胞生物学。
3
    台湾高雄I-Shou大学（燕巢校区）国际学生医学院。
4
    肝炎研究中心。
五
    免疫学研究所。
6
    微生物学系。
7
    生态与进化生物学研究所。
8
    内科。
9
    台湾大学医学院医学研究系，台湾大学医院。

抽象

为了解人类HBV感染的年龄依赖性结果的机制，我们以前建立了一个年龄相关的HBV小鼠模型，其中6周龄（N6W）C3H / HeN表现出病毒耐受性，而12周 - 旧（N12W）同行代表病毒清除。通过研究这两个年龄小鼠的肝髓细胞动态，我们的目标是确定与HBV清除相关的因素。通过流体动力学注射（HDI）用HBV质粒转染C3H / HeN小鼠。每周监测血清HBV标志物。在基线，注射后第3天（D3），D7和D14检查肝白细胞群及其细胞因子/趋化因子产生。分别向N12W和N6W小鼠施用CCR2拮抗剂和氯膦酸盐，以研究Ly6C +单核细胞和枯否细胞（KCs）在病毒清除中的作用。在HBV转染后，12周龄小鼠肝脏中D3分泌的TNF-α数量显着高于单核细胞和分泌IL-10的KCs少于其年轻的N6W对应物。此外，D7中IFNγ+TNFα+ CD8 + T细胞数量的增加仅见于较老的队列。 N12W中增强的Ly6C +单核细胞诱导是由肝细胞分泌的CCL2升高引起的。 CCR2拮抗剂给药阻碍了12周龄动物的Ly6C +单核细胞募集和KC降低程度，并延迟了HBV清除。氯膦酸脂质体对KCs的消耗增强了6周龄小鼠的Ly6C +单核细胞募集和加速HBV​​清除。结论：Ly6C +单核细胞和KCs可分别代表宿主防御的抗性和耐受性。这两种细胞类型在确定HBV清除率/耐受性中起着重要作用。操纵这些细胞是HBV相关肝病免疫治疗的有希望的途径。本文受版权保护。版权所有。

本文受版权保护。版权所有。
关键词：

细胞凋亡;干扰素γ;巨噬细胞; Toll样受体4;肿瘤坏死因子-α

结论：
    30661248
DOI：
    10.1002 / hep.30510