Our data provide strong evidence that HBV viral particles themselves can readily inhibit host innate immune responses upon virion/cell interactions, and may explain, at least partially, the "stealthy" character of HBV.

No 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.

The liver is the largest gland in the human body and functions as an innate immune organ. Liver macrophages called Kupffer cells (KC) constitute the largest group of macrophages in the human body. Innate immune responses involving KC represent the first line of defense against pathogens in the liver. Human monocyte-derived macrophages have been used to characterize inflammasome responses that lead to the release of the proinflammatory cytokines IL-1β and IL-18, but it has not yet been determined whether human KC contain functional inflammasomes. We show, to our knowledge for the first time, that KC express genes and proteins that make up several different inflammasome complexes. Moreover, activation of KC in response to the absent in melanoma 2 (AIM2) inflammasome led to the production of IL-1β and IL-18, which activated IL-8 transcription and hepatic NK cell activity, respectively. Other inflammasome responses were also activated in response to selected bacteria and viruses. However, hepatitis B virus inhibited the AIM2 inflammasome by reducing the mRNA stability of IFN regulatory factor 7, which regulated AIM2 transcription. These data demonstrate the production of IL-1β and IL-18 in KC, suggesting that KC contain functional inflammasomes that could be important players in the innate immune response following certain infections of the liver. We think our findings could potentially aid therapeutic approaches against chronic liver diseases that activate the inflammasome.

Different liver cell types are endowed with immunological properties, including cell-intrinsic innate immune functions that are important to initially control pathogen infections. However, a full landscape of expression and functionality of the innate immune signaling pathways in the major human liver cells is still missing. In order to comparatively characterize these pathways, we purified primary human hepatocytes, hepatic stellate cells, liver sinusoidal endothelial cells (LSEC), and Kupffer cells (KC) from human liver resections. We assessed mRNA and protein expression level of the major innate immune sensors, as well as checkpoint-inhibitor ligands in the purified cells, and found Toll-like receptors (TLR), RIG-I-like receptors, as well as several DNA cytosolic sensors to be expressed in the liver microenvironment. Amongst the cells tested, KC were shown to be most broadly active upon stimulation with PRR ligands emphasizing their predominant role in innate immune sensing the liver microenvironment. By KC immortalization, we generated a cell line that retained higher innate immune functionality as compared to THP1 cells, which are routinely used to study monocyte/macrophages functions. Our findings and the establishment of the KC line will help to understand immune mechanisms behind antiviral effects of TLR agonists or checkpoint inhibitors, which are in current preclinical or clinical development.

The hepatitis B virus (HBV) infects hepatocytes, which are the main cell type composing a human liver. However, the liver is enriched with immune cells, particularly innate cells (e.g., myeloid cells, natural killer and natural killer T-cells (NK/NKT), dendritic cells (DCs)), in resting condition. Hence, the study of the interaction between HBV and innate immune cells is instrumental to: (1) better understand the conditions of establishment and maintenance of HBV infections in this secondary lymphoid organ; (2) define the role of these innate immune cells in treatment failure and pathogenesis; and (3) design novel immune-therapeutic concepts based on the activation/restoration of innate cell functions and/or innate effectors. This review will summarize and discuss the current knowledge we have on this interplay between HBV and liver innate immunity.

The Hepatitis B virus chronically infects the liver of 250 million people worldwide. Over

Nuclear pRelA translocation in hepatocytes Highlights LCMV infection activates NF-jB signaling in hepatocytes. Macrophages, TNFR1 signaling do not induce LCMV-driven hepatocyte NF-jB-activation. Ikkb DHep mice display increased viral infection/replication and lower ISG induction. Ifnar DHep mice recapitulate aberrant virus replication as observed in Ikkb DHep mice. NF-jB signaling is required for efficient ISG induction in HBV-/HDV-infected HepaRG.