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

• DOI: 10.1016/j.jhep.2019.06.032
• Publication Date: 2019-07-23T15:27:00Z
• Authors: Suzanne Faure-Dupuy; Marion Delphin; Ludovic Aillot; Laura Dimier; Fanny Lebossé; Judith Fresquet; Romain Parent; Matthias Sebastia...; Michel Rivoire; Nathalie Bendriss...; Anna Salvetti; Danijela Heide; Lalo Flores; Klaus Klumpp; Angela Lam; Fabien Zoulim; Mathias Heikenwälder; David Durantel; Julie Lucifora
• Keywords: Anti-viral effect; MESH: Cell Differentiation; 0301 basic medicine; Hepatitis B virus; MESH: Interleukin-10; MESH: Hepatitis B, Chronic; Kupffer Cells; Interleukin-1beta; MESH: Immunomodulation; MESH: Monocytes; [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity; Monocytes; Phenotypic immune-modulation; Immunomodulation; phenotypic immune-modulation; 03 medical and health sciences; Hepatitis B, Chronic; MESH: Interleukin-1beta; [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases; Humans; Hepatitis B virus (HBV); Mononuclear Phagocyte System; Cells, Cultured; anti-inflammatory; MESH: Humans; MESH: Mononuclear Phagocyte System; MESH: Macrophage Activation; MESH: Immunohistochemistry; [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology; Cell Differentiation; Liver macrophage; Macrophage Activation; anti-viral effect; Immunohistochemistry; MESH: DNA, Viral; Interleukin-10; 3. Good health; MESH: Hepatitis B virus; MESH: Kupffer Cells; [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology; hepatitis B virus (HBV); IL-1β; IL-10; [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology; DNA, Viral; Anti-inflammatory; MESH: Cells, Cultured

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.