Aggravation of viral hepatitis by platelet-derived serotonin

Abstract

More than 500 million people worldwide are persistently infected with hepatitis B virus or hepatitis C virus 1 . 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 infection [1][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.Infection of mice with the noncytopathic lymphocytic choriomeningitis virus (LCMV) caused hepatocyte damage, as revealed by elevated serum alanin-aminotransferase (ALT) activities and serum bilirubin concentrations 5 (Fig. 1a). Virus-specific T cells are a major determinant of the outcome of hepatitis-these cells contribute to the early control of chronic hepatitis viruses and mediate immunopathology during persistent virus infection 1-4 . In a model of LCMV-induced hepatitis, complete depletion of CD8 + T cells enhanced virus replication, but strongly reduced hepatocyte damage (Fig. 1a), showing that the activation of virus-specific CD8 + T cells by viral antigen and not LCMV replication alone is responsible for liver cell damage, confirming earlier results 5,6 . To induce a delayed appearance of CD8 + T cells within the liver, we treated C57BL/6 mice with a 1:10 dilution of a CD8 cell-depleting antibody, which leads to a transient absence of CD8 + T cells. After 8-12 days, CD8 + T cells re-emerged (Fig. 1b). The delayed CD8 + T cell response within the liver was associated with prolonged viral replication and enhanced ALT levels in the serum when CD8 + T cells re-emerged (Fig. 1b).Therefore, similarly to the situation in human hepatitis 7-11 , delayed control of LCMV in the liver enhanced the overall immunopathology in the liver.Infection and virus-induced hepatitis have been linked to platelet activation [12][13][14] . To study the role of platelet activation in LCMVtriggered CD8 + T cell-dependent hepatiti...

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