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

Abstract

Background and aims. Liver macrophages can be both involved in 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 (PLM) and primary blood monocytes differentiated into pro-inflammatory or anti-inflammatory macrophages (M1-MDM or M2-MDM, respectively).Results. We evidenced the presence of HBc protein within macrophages in liver biopsies from HBV-infected patients and higher levels of anti-inflammatory macrophages markers, compared to non-infected ones. Ex vivo exposure of naive PLM to HBV led to a reduced secretion of proinflammatory cytokines. Upon exposure to HBV or HBV-producing cells during differentiation and activation, M1-MDM secreted less IL-6 and IL-1β, whereas M2-MDM secreted more IL-10 when exposed to HBV during activation. Finally, cytokines produced by M1-MDM, but not those produced by HBV-exposed M1-MDM, decreased HBV infection of hepatocytes.Conclusions. Altogether, our data strongly suggest that HBV modulates liver macrophage functions to favour its establishment. Lay summary: HBV modulates liver macrophages function in order to favour its establishment and likely its maintenance. 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 monocytes-derived-macrophages ex vivo by short exposure to the virus or cells replicating the virus, thus suggesting an "easy to implement" mechanism of inhibition.

Macrophage Phenotype and Function in Liver Disorder

“…In agreement with this hypothesis, Faure-Dupuy et al demonstrated that exposure to HBV attenuated cytokine release by pro-inflammatory hepatic macrophages and enhanced cytokine production by anti-inflammatory hepatic macrophages (65). This modulation suppresses the antiviral surveillance and favors the establishment of an infection (65). Taken together, a high HBV/HCV titer not only inhibits pro-inflammatory macrophage polarization but also promotes macrophages differentiating toward a tolerogenic phenotype, which favors HBV/HCV development by releasing immunoregulation cytokine IL-10.…”

“…It is likely that a high virus titer suppresses the antiviral activity of hepatic macrophages and polarizes hepatic macrophages toward a tolerogenic phenotype. In agreement with this hypothesis, Faure-Dupuy et al demonstrated that exposure to HBV attenuated cytokine release by pro-inflammatory hepatic macrophages and enhanced cytokine production by anti-inflammatory hepatic macrophages (65). This modulation suppresses the antiviral surveillance and favors the establishment of an infection (65).…”

“…Additionally, it has been shown that KCs may eliminate infected hepatocytes by releasing cytotoxic molecules, such as granzyme B, perforin, ROS, TRAIL, and Fas ligand (63,64) (Figure 2A). Furthermore, the supernatant from differentiated pro-inflammatory macrophages contains reasonable amounts of IL-1β and IL-6, which inhibit the progression of HBV by decreasing levels of hepatitis B surface antigen (HBsAg) and hepatitis B early antigen (HBeAg) (65).…”

Insights for clinical diagnostic indicators of virus and host in chronic hepatitis B infection

“…The level of anti‐inflammatory macrophages maker, IL‐10, was higher when exposed to HBV while pro‐inflammatory cytokines (IL‐6 and IL‐1β) were downregulated. This phenotype was similar in monocytes‐derived macrophages . Li et al suggested that HBsAg enabled monocytes to highly express cell surface inhibitors (PD‐L1 and HLA‐E) and anti‐inflammatory factors (TNF‐α, TGF‐β and IL‐10) to interact with NK cells, which led to regulatory NK cells differentiation, further inhibited T‐cell activation.…”

Macrophage Phenotypes and Hepatitis B Virus Infection

“…The distinct roles of M1 and M2 macrophages involved in HBV infection raise the possibility that HBV may promote M2 polarization of macrophages to impair the Type 1 T helper cell immune response, resulting in persistent infection and disease progression. A most recent study 87 supported the hypothesis that HBV suppresses M1 macrophage cytokine (IL-6 and IL-1b) expression and promotes M2 macrophage cytokine (IL-10) expression to favor HBV infection. Although the precise mechanism remains unclear, several in vitro studies have revealed that either hepatitis B surface antigen or hepatitis B e antigen may make a contribution.…”