Aggravation of viral hepatitis by platelet-derived serotonin.
More than 500 million people worldwide are persistently infected with hepatitis B virus or hepatitis C virus. 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. 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.
Institute of Experimental Immunology, University Hospital of Zurich, Schmelzberstrasse 12, CH-8091 Zurich, Switzerland.
Philipp A
PA
Lang
Claudio
C
Contaldo
Panco
P
Georgiev
Ashraf Mohammad
AM
El-Badry
Mike
M
Recher
Michael
M
Kurrer
Luisa
L
Cervantes-Barragan
Burkhard
B
Ludewig
Thomas
T
Calzascia
Beatrice
B
Bolinger
Doron
D
Merkler
Bernhard
B
Odermatt
Michael
M
Bader
Rolf
R
Graf
Pierre-Alain
PA
Clavien
Ahmed N
AN
Hegazy
Max
M
Löhning
Nicola L
NL
Harris
Pamela S
PS
Ohashi
Hans
H
Hengartner
Rolf M
RM
Zinkernagel
Karl S
KS
Lang
D000818:Animals; D001792:Blood Platelets / Q000737:chemistry*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D006207:Half-Life; D006524:Hepatitis, Viral, Animal / Q000276:immunology / Q000473:pathology* / Q000821:virology; D008099:Liver / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D008216:Lymphocytic Choriomeningitis / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation; D010976:Platelet Count; D012701:Serotonin / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
D012701:Serotonin