乙肝病毒诱导的肝巨噬细胞功能调节促进肝细胞感染

StephenW

Hepatitis B virus-induced modulation of liver macrophage function promotes hepatocyte infection
Suzanne Faure-Dupuy1,2,†
, Marion Delphin1,†
, Ludovic Aillot1
, Laura Dimier1
, Fanny Lebossé1,3
, Judith Fresquet1
, Romain Parent1
, Matthias Sebastian Matter4
, Michel Rivoire5
, Nathalie Bendriss-Vermare1
, Anna Salvetti1
, Danijela Heide2
, Lalo Flores6
, Klaus Klumpp6
, Angela Lam6
, Fabien Zoulim1,3,7
, Mathias Heikenwälder2
, David Durantel1,7,low asterisk,'Correspondence information about the author David Durantel‡,Email the author David Durantel
, Julie Lucifora1,low asterisk,'Correspondence information about the author Julie Lucifora‡,Email the author Julie Lucifora
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DOI: https://doi.org/10.1016/j.jhep.2019.06.032 |

Highlights

    •Hepatitis B virus proteins are observed in liver macrophages from patients.
    •Hepatitis B virus impairs pro-inflammatory macrophage secretion.
    •Hepatitis B virus increases anti-inflammatory macrophage secretion.
    •Impairment of pro-inflammatory secretions favours the establishment of hepatitis B virus infection.
    •Increase of IL-10 secretion further impairs lymphocyte activation.

Background & Aims

Liver macrophages can be involved in both pathogen clearance and/or pathogenesis. To get further insight on their role during chronic hepatitis B virus (HBV) infections, our aim was to phenotypically and functionally characterize in vivo and ex vivo the interplay between HBV, primary human liver macrophages (PLMs) and primary blood monocytes differentiated into pro-inflammatory or anti-inflammatory macrophages (M1-MDMs or M2-MDMs, respectively).
Methods

PLMs or primary blood monocytes, either ex vivo differentiated into M1-MDMs or M2-MDMs, were exposed to HBV and their activation followed by ELISA or quantitative reverse transcription PCR (RT-qPCR). Liver biopsies from HBV-infected patients were analysed by RT-qPCR or immunohistochemistry. Viral parameters in HBV-infected primary human hepatocytes and differentiated HepaRG cells were followed by ELISA, qPCR and RT-qPCR analyses.
Results

HBc protein was present within the macrophages of liver biopsies taken from HBV-infected patients. Macrophages from HBV-infected patients also expressed higher levels of anti-inflammatory macrophage markers than those from non-infected patients. Ex vivo exposure of naive PLMs to HBV led to reduced secretion of pro-inflammatory cytokines. Upon exposure to HBV or HBV-producing cells during differentiation and activation, M1-MDMs secreted less IL-6 and IL-1β, whereas M2-MDMs secreted more IL-10 when exposed to HBV during activation. Finally, cytokines produced by M1-MDMs, but not those produced by HBV-exposed M1-MDMs, decreased HBV infection of hepatocytes.
Conclusions

Altogether, our data strongly suggest that HBV modulates liver macrophage functions to favour the establishment of infection.
Lay summary

Hepatitis B virus modulates liver macrophage function in order to favour the establishment and likely maintenance of infection. It impairs the production of the antiviral cytokine IL-1β, while promoting that of IL-10 in the microenvironment. This phenotype can be recapitulated in naive liver macrophages or monocyte-derived-macrophages ex vivo by short exposure to the virus or cells replicating the virus, thus suggesting an “easy to implement” mechanism of inhibition.
Keywords:
Liver macrophage, Hepatitis B virus (HBV), Phenotypic immune-modulation, IL-1β, IL-10, Anti-inflammatory, Anti-viral effect

StephenW

乙肝病毒诱导的肝巨噬细胞功能调节促进肝细胞感染
苏珊娜·佛瑞-杜普伊1,2，†
，马里恩·德尔芬（Marion Delphin1），†
，卢多维克·艾略特1
劳拉·迪米（Laura Dimier）1
，范妮·勒博塞1,3
，朱迪思·弗雷斯奎1
罗曼（Romain）Parent1
，Matthias Sebastian Matter4
，米歇尔·里沃瓦（Michel Rivoire）5
，娜塔莉（Nathalie Bendriss-Vermare）1
安娜·萨尔瓦蒂（Anna Salvetti）1
，Danijela Heide2
，拉洛·弗洛雷斯6
，克劳斯·克鲁姆普6
，安吉拉（Angela Lam）6
，Fabien Zoulim1,3,7
，MathiasHeikenwälder2
，David Durantel1,7，低星号，关于作者David Durantel‡的通讯信息，向作者发送电子邮件David Durantel
，Julie Lucifora1，low asterisk，'有关作者Julie Lucifora‡的通讯信息，向作者发送电子邮件给Julie Lucifora
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DOI：https：//doi.org/10.1016/j.jhep.2019.06.032 |

强调

    •在患者的肝巨噬细胞中观察到乙型肝炎病毒蛋白。
    •乙型肝炎病毒损害促炎性巨噬细胞分泌。
    •乙型肝炎病毒可增加抗炎巨噬细胞的分泌。
    •促炎性分泌物的受损有助于建立乙型肝炎病毒感染。
    •IL-10分泌增加进一步损害淋巴细胞活化。

背景与目标

肝巨噬细胞可参与病原体清除和/或发病机理。为了进一步了解其在慢性乙型肝炎病毒（HBV）感染中的作用，我们的目标是在体内和离体表型和功能上表征HBV，原代人肝巨噬细胞（PLM）和原代肝单核细胞之间的相互作用。炎性或抗炎性巨噬细胞（分别为M1-MDM或M2-MDM）。
方法

将离体分化为M1-MDM或M2-MDM的PLM或原代血液单核细胞暴露于HBV中，并对其进行激活，然后进行ELISA或定量逆转录PCR（RT-qPCR）。通过RT-qPCR或免疫组织化学分析了HBV感染患者的肝活检。通过ELISA，qPCR和RT-qPCR分析追踪HBV感染的原代人肝细胞和分化的HepaRG细胞的病毒参数。
结果

HBc蛋白存在于取自HBV感染患者的肝活检标本中。来自HBV感染患者的巨噬细胞也表达了比未感染患者更高的抗炎巨噬细胞标志物水平。原始PLM的离体暴露于HBV导致促炎性细胞因子的分泌减少。在分化和激活过程中接触HBV或产生HBV的细胞后，M1-MDMs分泌较少的IL-6和IL-1β，而M2-MDMs在激活过程中接触HBV分泌更多的IL-10。最后，由M1-MDM产生的细胞因子而非暴露于HBV的M1-MDM产生的细胞因子减少了肝细胞的HBV感染。
结论

总而言之，我们的数据强烈表明HBV调节肝巨噬细胞功能以促进感染的建立。
放置摘要

乙型肝炎病毒调节肝巨噬细胞功能，以促进感染的建立和维持。它削弱了抗病毒细胞因子IL-1β的产生，同时在微环境中促进了IL-10的产生。通过短暂暴露于病毒或复制病毒的细胞中，可以在离体的幼稚肝巨噬细胞或单核细胞衍生的巨噬细胞中概括这种表型，从而表明了抑制的“易于实施”的机制。
关键字：
肝巨噬细胞，乙型肝炎病毒（HBV），表型免疫调节，IL-1β，IL-10，抗炎，抗病毒作用