Innate Immune Responses in Viral Hepatitis: the role of Kupffer cells and liver-derived monocytes in shaping intrahepatic immunity in mice using the LCMV infection model

Abstract

This study was performed to elucidate the immunological role of the liver in viral hepatitis. The immune functions of the liver are shaped by the intrahepatic cells present during steady state condition, as well as the recruited immune cells during liver inflammation. Liver resident Kupffer cells, by performing endocytosis, determine the functionality of the liver as a filtering organ. Additionally, Kupffer cells produce IL-10. This function, regulated by Ctcf, suggests the potential of Kupffer cells to perform immunoregulation. Monocytes patrol the liver in the steady state, but accumulate in the liver during viral hepatitis. They show functional versatility as demonstrated in the distinct polarization towards TNF-producing and endocytic cells in LCMV-infected and LPS-treated livers, respectively. During LCMV-induced hepatitis, fractions of both Kupffer cells and inflammatory monocytes alter their F4/80 expression, posing a challenge in immunological studies using flow cytometry. Furthermore, in this study we describe distinct clinical responses induced by TLR7 treatment at different phases of LCMV infection, which are associated with distinct states of immune activation. Results from our study contribute to better understand the regulation of intrahepatic immune responses in the steady state condition and during viral hepatitis. Better insights in the functions of Kupffer cells and inflammatory monocytes will open up their potential to be targeted by HBV and HCV therapy. Furthermore, this study emphasizes the importance of characterizing the intrahepatic immune responses during chronic viral hepatitis to understand the mechanisms for the induction of adverse side-effects by TLR7 treatment. This information is valuable in order to prevent or predict the clinical outcome of TLR7-based treatment of HBV or HCV patients. Although this need to be validated in more detail, our findings suggest the significance of evaluating the TLR7 expression levels, either intrahepatic or systemic, in chronically infected patients prior to TLR7 treatment to minimalize the occurrence of adverse side-effects.