title: Inflammatory monocytes recruited to the liver within 24 hours after virus-induced inflammation resemble Kupffer cells but are functionally distinct.
abstract: Due to a scarcity of immunocompetent animal models for viral hepatitis, little is known about the early innate immune responses in the liver. In various hepatotoxic models, both pro- and anti-inflammatory activities of recruited monocytes have been described. In this study, we compared the effect of liver inflammation induced by the Toll-like receptor 4 ligand lipopolysaccharide (LPS) with that of a persistent virus, lymphocytic choriomeningitis virus (LCMV) clone 13, on early innate intrahepatic immune responses in mice. LCMV infection induces a remarkable influx of inflammatory monocytes in the liver within 24 h, accompanied by increased transcript levels of several proinflammatory cytokines and chemokines in whole liver. Importantly, while a single LPS injection results in similar recruitment of inflammatory monocytes to the liver, the functional properties of the infiltrating cells are dramatically different in response to LPS versus LCMV infection. In fact, intrahepatic inflammatory monocytes are skewed toward a secretory phenotype with impaired phagocytosis in LCMV-induced liver inflammation but exhibit increased endocytic capacity after LPS challenge. In contrast, F4/80(high)-Kupffer cells retain their steady-state endocytic functions upon LCMV infection. Strikingly, the gene expression levels of inflammatory monocytes dramatically change upon LCMV exposure and resemble those of Kupffer cells. Since inflammatory monocytes outnumber Kupffer cells 24 h after LCMV infection, it is highly likely that inflammatory monocytes contribute to the intrahepatic inflammatory response during the early phase of infection. Our findings are instrumental in understanding the early immunological events during virus-induced liver disease and point toward inflammatory monocytes as potential target cells for future treatment options in viral hepatitis.
  
  
  OBJECTIVE
  Insights into how the immune system deals with hepatitis B virus (HBV) and HCV are scarce due to the lack of adequate animal model systems. This knowledge is, however, crucial to developing new antiviral strategies aimed at eradicating these chronic infections. We model virus-host interactions during the initial phase of liver inflammation 24 h after inoculating mice with LCMV. We show that infected Kupffer cells are rapidly outnumbered by infiltrating inflammatory monocytes, which secrete proinflammatory cytokines but are less phagocytic. Nevertheless, these recruited inflammatory monocytes start to resemble Kupffer cells on a transcript level. The specificity of these cellular changes for virus-induced liver inflammation is corroborated by demonstrating opposite functions of monocytes after LPS challenge. Overall, this demonstrates the enormous functional and genetic plasticity of infiltrating monocytes and identifies them as an important target cell for future treatment regimens.
authors: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Dowty
authors: D
authors: Movita
authors: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Martijn D B
authors: http://orcid.org/0000-0003-0509-7713
authors: MD
authors: van de Garde
authors: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Paula
authors: P
authors: Biesta
authors: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Kim
authors: K
authors: Kreefft
authors: Department of Viroscience, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Bart
authors: B
authors: Haagmans
authors: Division of Biological Sciences, University of California San Diego, La Jolla, San Diego, California.
authors: Elina
authors: E
authors: Zuniga
authors: Janssen Infectious Disease and Drug Safety Sciences, Beerse, Belgium.
authors: Florence
authors: F
authors: Herschke
authors: Janssen Infectious Disease and Drug Safety Sciences, Beerse, Belgium.
authors: Sandra
authors: S
authors: De Jonghe
authors: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands Liver Clinic, Toronto Western and General Hospital University Health Network Toronto, Toronto, Canada.
authors: Harry L A
authors: HL
authors: Janssen
authors: Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Lucio
authors: L
authors: Gama
authors: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Andre
authors: A
authors: Boonstra
authors: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands t.vanwolleghem@erasmusmc.nl.
authors: Thomas
authors: T
authors: Vanwolleghem
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D020869:Gene Expression Profiling; D006524:Hepatitis, Viral, Animal / Q000473:pathology*; D007728:Kupffer Cells / Q000276:immunology*; D008099:Liver / Q000473:pathology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology*
chemical_list: D016207:Cytokines