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Hepatitis B virus-induced modulation of liver macrophage function promotes hepatocyte infection

肝细胞 离体 巨噬细胞 病毒 乙型肝炎病毒 乙型肝炎 体内 炎症 免疫学 病毒学 生物 体外 生物化学 生物技术
作者
Suzanne Faure‐Dupuy,Marion Delphin,Ludovic Aillot,Laura Dimier,Fanny Lebossé,Judith Fresquet,Romain Parent,Matthias S. Matter,Michel Rivoire,Nathalie Bendriss‐Vermare,Anna Salvetti,Danijela Heide,Lalo Flores,Klaus Klumpp,Angela M. Lam,Fabien Zoulim,Mathias Heikenwälder,David Durantel,Julie Lucifora
出处
期刊:Journal of Hepatology [Elsevier BV]
卷期号:71 (6): 1086-1098 被引量:83
标识
DOI:10.1016/j.jhep.2019.06.032
摘要

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