On the role of platelets in the pathogenesis of viral hepatitis (2009)

We read with interest the commentary by Ulrich Spengler [[1]Spengler U. Hepatic microcirculation – a critical but neglected factor for the outcome of viral hepatitis.J Hepatol. 2009; 50: 631-633Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar] where he evaluated a recent manuscript by Lang et al. [[2]Lang P.A. Contaldo C. Georgiev P. El-Badry A. Recher M. Kurrer M. et al.Aggravation of viral hepatitis by platelet-derived serotonin.Nat Med. 2008; 14: 756-761Crossref PubMed Scopus (195) Google Scholar] on the role of platelet-derived serotonin in the pathogenesis of viral hepatitis. We were somewhat surprised to see that work constituting the foundation of the above-mentioned study was not cited. A few years ago our group started investigating the role of platelets in the pathogenesis of viral hepatitis, using different mouse models that include transgenic mice replicating hepatitis B virus (HBV) at high levels in the hepatocyte and mice infected with hepatotropic adenoviruses and arenaviruses (i.e. lymphocytic choriomeningitis virus [LCMV]). Similar to humans infected with HBV or hepatitis C virus (HCV), liver disease in these models is mostly a consequence of the virus-specific CD8 T cell response aimed at viral clearance. We found that platelets play a previously unrecognized role in viral hepatitis. Upon activation, platelets contribute to liver disease and viral clearance by promoting the recruitment of virus-specific cytotoxic T lymphocytes (CTL) into the liver [[3]Iannacone M. Sitia G. Isogawa M. Marchese P. Castro M.G. Lowenstein P.R. et al.Platelets mediate cytotoxic T lymphocyte-induced liver damage.Nat Med. 2005; 11: 1167-1169Crossref PubMed Scopus (283) Google Scholar]. Further experiments suggested that this effect depends on specific interactions between platelets and CTL likely occurring within the hepatic microcirculation and helping CTL to extravasate, reach target cells and perform pathogenic and antiviral effector functions [4Iannacone M. Sitia G. Ruggeri Z.M. Guidotti L.G. HBV pathogenesis in animal models: recent advances on the role of platelets.J Hepatol. 2007; 46: 719-726Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 5Iannacone M. Sitia G. Guidotti G.L. Pathogenetic and antiviral immune responses against hepatitis B virus.Future Virology. 2006; 1: 189-196Crossref Google Scholar, 6Guidotti L.G. Chisari F.V. Immunobiology and pathogenesis of viral hepatitis.Annu Rev Pathol. 2006; 1: 23-61Crossref PubMed Scopus (611) Google Scholar]. We confirmed these results in follow-up studies by showing reduction of hepatic CTL recruitment after pharmacological inhibition of platelet activation [[7]Iannacone M. Sitia G. Narvaiza I. Ruggeri Z.M. Guidotti L.G. Antiplatelet therapy inhibits immune-mediated liver disease and viral clearance in mice infected with a replication-deficient adenovirus.Clin Vaccine Immunol. 2007; 14: 1532-1535Crossref PubMed Scopus (43) Google Scholar]. The paper by Lang et al. nicely reiterates a role for platelets in the pathogenesis of liver disease and provides a novel mechanistic hint. They identified serotonin as a potential molecular mediator of CTL recruitment and liver damage in LCMV-infected mice. Although the use of LCMV as a model for human HBV and HCV infection must be taken cautiously (unlike HBV and HCV that infect hepatocytes almost exclusively, LCMV infects primarily non-parenchymal cells of the liver such as Kupffer cells [[8]Guidotti L.G. Borrow P. Hobbs M.V. Matzke B. Gresser I. Oldstone M.B. et al.Viral cross talk: intracellular inactivation of the hepatitis B virus during an unrelated viral infection of the liver.Proc Natl Acad Sci USA. 1996; 93: 4589-4594Crossref PubMed Scopus (179) Google Scholar]), the study by Lang et al. raises important questions. Where does serotonin come from during liver inflammation? Is it platelet-derived as the authors seem to suggest? What cells respond to serotonin? What serotonin receptors are involved? The answers to these questions are important if we envisage future manipulations of serotonin-dependent pathways designed to either counteract excessive liver damage or, conversely, promote the hepatic homing and antiviral potential of CTL induced by therapeutic vaccines. In addition to serotonin, it is likely that other platelet-derived molecular mediators of liver damage will be discovered in the years to come, allowing us to better understand the complex interplay between platelets and CTL in the inflamed liver microenvironment.