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Aggravation of viral hepatitis by platelet-derived serotonin

Nature Medicine volume 14, pages 756–761 (2008)Cite this article

Abstract

More than 500 million people worldwide are persistently infected with hepatitis B virus or hepatitis C virus1. Although both viruses are poorly cytopathic, persistence of either virus carries a risk of chronic liver inflammation, potentially resulting in liver steatosis, liver cirrhosis, end-stage liver failure or hepatocellular carcinoma. Virus-specific T cells are a major determinant of the outcome of hepatitis, as they contribute to the early control of chronic hepatitis viruses, but they also mediate immunopathology during persistent virus infection1,2,3,4. We have analyzed the role of platelet-derived vasoactive serotonin during virus-induced CD8+ T cell–dependent immunopathological hepatitis in mice infected with the noncytopathic lymphocytic choriomeningitis virus. After virus infection, platelets were recruited to the liver, and their activation correlated with severely reduced sinusoidal microcirculation, delayed virus elimination and increased immunopathological liver cell damage. Lack of platelet-derived serotonin in serotonin-deficient mice normalized hepatic microcirculatory dysfunction, accelerated virus clearance in the liver and reduced CD8+ T cell–dependent liver cell damage. In keeping with these observations, serotonin treatment of infected mice delayed entry of activated CD8+ T cells into the liver, delayed virus control and aggravated immunopathological hepatitis. Thus, vasoactive serotonin supports virus persistence in the liver and aggravates virus-induced immunopathology.

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Figure 1: LCMV infection results in platelet activation and reduced blood flow within the liver.
Figure 2: Platelet-derived serotonin mediates LCMV-induced reductions in liver blood flow.
Figure 3: Serotonin has no impact on CD8+ T cell priming.
Figure 4: Exogenous serotonin aggravates viral hepatitis.

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Acknowledgements

We would like to thank I. Miescher for technical support and A. Fitsche, I. Markewitz, A. Helminski and S. Behnke for histological analysis. This study was supported by the Swiss National Science Foundation grants 3100A0-100779 (to H.H.) and 3100A0-100068 (to R.M.Z.) and the Canadian Institutes of Health Research grant to P.S.O. K.S.L. was partially supported by the Jung-Stiftung für Wissenschaft und Forschung. P.A.L. was supported by SFB/Transregio6040. A.N.H. is a fellow of GRAKO1121 of the German Research Foundation. M.L. is a Lichtenberg fellow funded by the Volkswagen Foundation.

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Author notes

  1. Philipp A Lang, Claudio Contaldo and Panco Georgiev: These authors contributed equally to this work.

  2. Rolf M Zinkernagel and Karl S Lang: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Experimental Immunology, University Hospital of Zurich, Schmelzberstrasse 12, Zurich, CH-8091, Switzerland

    Philipp A Lang, Mike Recher, Doron Merkler, Ahmed N Hegazy, Max Löhning, Nicola L Harris, Hans Hengartner, Rolf M Zinkernagel & Karl S Lang

  2. Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, UHN, 620 University Avenue, Toronto, M5G 2C1, Ontario, Canada

    Philipp A Lang, Thomas Calzascia, Pamela S Ohashi & Karl S Lang

  3. Division of Plastic and Reconstructive Surgery, University Hospital of Zurich, Schmelzberstrasse 12, Zurich, CH-8091, Switzerland

    Claudio Contaldo

  4. Department of Surgery, Swiss Hepato-Pancreato-Biliary Center, University Hospital of Zurich, Schmelzberstrasse 12, Zurich, CH-8091, Switzerland

    Panco Georgiev, Ashraf Mohammad El-Badry, Rolf Graf & Pierre-Alain Clavien

  5. Department of Surgical Pathology, University Hospital of Zurich, Schmelzberstrasse 12, Zurich, CH-8091, Switzerland

    Michael Kurrer & Bernhard Odermatt

  6. Research Department, Kantonal Hospital St Gallen, Rorschacher Strasse 95, St Gallen, CH-9007, Switzerland

    Luisa Cervantes-Barragan, Burkhard Ludewig & Beatrice Bolinger

  7. Institute of Neuropathology, Georg August University Göttingen, Robert-Koch-Strasse 40, Göttingen, D-37075, Germany

    Doron Merkler

  8. Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, Berlin-Buch, 13125, Germany

    Michael Bader

  9. Department of Rheumatology and Clinical Immunology, Charité–University Medicine Berlin and Deutsches Rheuma-Forschungszentrum Berlin, Schumannstrasse 21-22, Berlin, 10117, Germany

    Ahmed N Hegazy & Max Löhning

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  1. Philipp A Lang
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Contributions

P.A.L., C.C. and P.G. planned and performed most experiments. A.M.E.-B. performed hepatic microcirculation experiments. D.M., B.O. and M.K. performed and analyzed histology. L.C.-B., B.L. and B.B. performed adenovirus and mouse hepatitis virus experiments. T.C. and A.N.H. performed some experiments. M.B., R.G., P.-A.C., M.L. and N.L.H. discussed and interpreted results. M.R., P.S.O. and H.H. came up with ideas and helped write the manuscript. R.M.Z. and K.S.L. designed the study and wrote the manuscript.

Corresponding authors

Correspondence to Rolf M Zinkernagel or Karl S Lang.

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Lang, P., Contaldo, C., Georgiev, P. et al. Aggravation of viral hepatitis by platelet-derived serotonin. Nat Med 14, 756–761 (2008). https://doi.org/10.1038/nm1780

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