1. Hepatitis B virus-induced modulation of liver macrophage function promotes hepatocyte infection
- Author
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Michel Rivoire, Angela Lam, Romain Parent, Nathalie Bendriss-Vermare, Danijela Heide, Julie Lucifora, Matthias S. Matter, Ludovic Aillot, Klaus Klumpp, Fabien Zoulim, Fanny Lebossé, Lalo Flores, Laura Dimier, Judith Fresquet, Anna Salvetti, Suzanne Faure-Dupuy, David Durantel, Marion Delphin, Mathias Heikenwalder, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), ANRS, Lucifora, Julie, and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Anti-viral effect ,MESH: Interleukin-10 ,medicine.medical_treatment ,Interleukin-1beta ,medicine.disease_cause ,MESH: Monocytes ,[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity ,Monocytes ,0302 clinical medicine ,MESH: Interleukin-1beta ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Macrophage ,Mononuclear Phagocyte System ,Cells, Cultured ,anti-inflammatory ,[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,virus diseases ,MESH: Macrophage Activation ,Cell Differentiation ,Liver macrophage ,Immunohistochemistry ,Interleukin-10 ,3. Good health ,Interleukin 10 ,MESH: Hepatitis B virus ,medicine.anatomical_structure ,Cytokine ,[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology ,IL-1β ,[SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology ,Hepatocyte ,IL-10 ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,030211 gastroenterology & hepatology ,MESH: Cells, Cultured ,MESH: Cell Differentiation ,Hepatitis B virus ,Kupffer Cells ,MESH: Hepatitis B, Chronic ,MESH: Immunomodulation ,Biology ,Virus ,Immunomodulation ,Phenotypic immune-modulation ,03 medical and health sciences ,Hepatitis B, Chronic ,In vivo ,medicine ,Humans ,Hepatitis B virus (HBV) ,[SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity ,MESH: Humans ,MESH: Mononuclear Phagocyte System ,Hepatology ,MESH: Immunohistochemistry ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,Macrophage Activation ,[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,digestive system diseases ,MESH: DNA, Viral ,030104 developmental biology ,MESH: Kupffer Cells ,DNA, Viral ,Immunology ,Ex vivo - Abstract
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.
- Published
- 2019