Impact of intercellular communication between macrophages and hepatocytes on their responses towards CMV or LPS

Background & aims Macrophages are key components of the innate immune response. With high plasticity they adapt their phenotype to distinct challenges. As first responders towards pathogens they express inflammatory cytokines and chemokines that regulate responses of the cellular microenvironment within the liver. Hepatocytes represent a prime site of viral replication upon cytomegalovirus (CMV) infection. So far it is unknown, how macrophages impede viral replication in hepatocytes or if at all. Contrariwise, the impact of hepatocytes on the macrophages” phenotype in case of CMV infection remains to be elucidated. In addition, similarities or differences between co-cultivated macrophages and hepatocytes after treatment with CMV or lipopolysaccharide (LPS) are not identified, yet. First, this study aims to evaluate the pathogen-induced molecular pattern that directs the intercellular communication between macrophages and hepatocytes. Second, the impact of macrophages on viral replication within hepatocytes is analyzed.

Methods Bone marrow derived macrophages (BMDM) and hepatocytes from wildtype mice were prepared. To analyze cytokine expression BMDM and hepatocytes were subjected to an in vitro co-culture system for 2 days. Afterwards cells were treated with UV-inactivated murine (M)CMV or LPS. To evaluate viral replication hepatocytes were infected with live MCMV and then co-cultivated with BMDM.

Results Following co-cultivation with hepatocytes BMDM express significantly increased Ly6G(C) and CD11c membrane proteins. Furthermore, these hepatocyte-directed BMDM show enhanced expression of pro-viral IL-10, but diminished expression of anti-viral IFN-β, IL-6 (also known as IFN-β2) and TNF-α after treatment with UV-inactivated MCMV. In accordance with this hepatocyte-directed BMDM also show enhanced IL-10 and diminished TNF-α levels upon stimulation with LPS, but in contrast to MCMV enhanced IFN-β and IL-6 expressions. Moreover, the presence of BMDM inhibits viral replication in MCMV-infected hepatocytes.

Conclusion Macrophages exert anti-viral effector functions on hepatocytes causing a reduction of viral replication in a co-cultivated in vitro system. However, the intercellular communication between hepatocytes and macrophages leads to a macrophage phenotype that promotes pro-viral, but reduces anti-viral characteristics. This indicates that hepatocytes impede anti-viral effector functions of macrophages, probably as a part of immune escape.

Publication History

Article published online:
04 January 2021