Tissue Macrophages Suppress Viral Replication and Prevent... : Hepatology (original) (raw)

Viral Hepatitis

Tissue Macrophages Suppress Viral Replication and Prevent Severe Immunopathology in an Interferon-I-Dependent Manner in Mice

Lang, Philipp A.1,2,*; Recher, Mike1; Honke, Nadine3; Scheu, Stefanie4; Borkens, Stephanie4; Gailus, Nicole3; Krings, Caroline3; Meryk, Andreas3; Kulawik, Andreas3; Cervantes-Barragan, Luisa5; Van Rooijen, Nico6; Kalinke, Ulrich7; Ludewig, Burkhard5; Hengartner, Hans1; Harris, Nicola8; Häussinger, Dieter3; Ohashi, Pamela S.2; Zinkernagel, Rolf M.1; Lang, Karl S.1,3,*

1_Institute of Experimental Immunology, University Hospital of Zurich, Zurich, Switzerland_

2_Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Canada_

3_Department of Gastroenterology, Hepatology, and Infectiology, University of Dusseldorf, Dusseldorf, Germany_

4_Institute of Medical Microbiology and Hospital Hygiene, University of Dusseldorf, Dusseldorf, Germany_

5_Institute of Immunobiology, Kantonal Hospital St. Gallen, St. Gallen, Switzerland_

6_Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, Amsterdam, The Netherlands_

7_TWINCORE, Centre for Experimental and Clinical Infection Research; Institute of Experimental Infection Research, Hannover, Germany_

8_Swiss Vaccine Research Institute c/o Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (Swiss Federal Institute of Technology) Lausanne, Switzerland_

*Address reprint requests to: Department of Hepatology and Infectiology, University of Dusseldorf, Universitätsstr. 1, Dusseldorf, Germany D-40225. E-mail:[email protected]or[email protected]

Received 26 October 2009; accepted 16 February 2010

Supported by Swiss National Science Foundation Grants 3100A0-100779 (to H. H.) and 3100A0-100068 (to R. M. Z.); Deutsche Forschungsgemeinschaft through SFB 575 “Experimental Hepatology” (to D. H.) and grant LA1419/3-1 (to K. S. L.); the Sofja Kovalevskaja Award from the Alexander von Humboldt-Foundation (to K.S.L); Canadian Institutes of Health Research Grant FRN 79434 (to P. S. O.); and German Research Foundation Grant SCHE692/3-1 (S. S.). P. S. O. holds a Canada Research Chair in Autoimmunity and Tumor Immunity.

Current address for M. R.: Institute of Clinical Immunology, University Hospital, Zurich, Switzerland

Published online in Wiley InterScience (www.interscience.wiley.com).

Potential conflict of interest: Nothing to report.

Additional Supporting Information may be found in the online version of this article.

Abstract

The innate immune response plays an essential role in the prevention of early viral dissemination. We used the lymphocytic choriomeningitis virus model system to analyze the role of tissue macrophages/Kupffer cells in this process. Our findings demonstrated that Kupffer cells are essential for the efficient capture of infectious virus and for preventing viral replication. The latter process involved activation of Kupffer cells by interferon (IFN)-I and prevented viral spread to neighboring hepatocytes. In the absence of Kupffer cells, hepatocytes were not able to suppress virus replication, even in the presence of IFN-I, leading to prolonged viral replication and severe T cell-dependent immunopathology.

Conclusion:

Tissue-resident macrophages play a crucial role in early viral capture and represent the major liver cell type exhibiting responsiveness to IFN-I and providing control of viral replication. (Hepatology 2010)