title: The receptor tyrosine kinase EphB2 promotes hepatic fibrosis in mice.
abstract: Beyond the well-defined role of the Eph (erythropoietin-producing hepatocellular) receptor tyrosine kinases in developmental processes, cell motility, cell trafficking/adhesion, and cancer, nothing is known about their involvement in liver pathologies. During blood-stage rodent malaria infection we have found that EphB2 transcripts and proteins were up-regulated in the liver, a result likely driven by elevated surface expression on immune cells including macrophages. This was significant for malaria pathogenesis because EphB2(-/-) mice were protected from malaria-induced liver fibrosis despite having a similar liver parasite burden compared with littermate control mice. This protection was correlated with a defect in the inflammatory potential of hepatocytes from EphB2(-/-) mice resulting in a reduction in adhesion molecules, chemokine/chemokine receptor RNA levels, and infiltration of leukocytes including macrophages/Kupffer cells, which mediate liver fibrosis during rodent malaria infections. These observations are recapitulated in the well-established carbon tetrachloride model of liver fibrosis in which EphB2(-/-) carbon tetrachloride-treated mice showed a significant reduction of liver fibrosis compared to carbon tetrachloride-treated littermate mice. Depletion of macrophages by clodronate-liposomes abrogates liver EphB2 messenger RNA and protein up-regulation and fibrosis in malaria-infected mice.
  
  
  CONCLUSIONS
  During rodent malaria, EphB2 expression promotes malaria-associated liver fibrosis; to our knowledge, our data are the first to implicate the EphB family of receptor tyrosine kinases in liver fibrosis or in the pathogenesis of malaria infection.
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA.
authors.forename: Patrice N
authors.initials: PN
authors.lastname: Mimche
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Brady
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA.
authors.forename: Christian F
authors.initials: CF
authors.lastname: Bray
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA.
authors.forename: Choon M
authors.initials: CM
authors.lastname: Lee
authors.affiliation: Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA.
authors.forename: Manoj
authors.initials: M
authors.lastname: Thapa
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA.
authors.forename: Thayer P
authors.initials: TP
authors.lastname: King
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA.
authors.forename: Kendra
authors.initials: K
authors.lastname: Quicke
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA.
authors.forename: Courtney D
authors.initials: CD
authors.lastname: McDermott
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA.
authors.forename: Sylvie M
authors.initials: SM
authors.lastname: Mimche
authors.affiliation: Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA.
authors.forename: Arash
authors.initials: A
authors.lastname: Grakoui
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Morgan
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA.
authors.forename: Tracey J
authors.initials: TJ
authors.lastname: Lamb
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology* / Q000502:physiology; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D022781:Hepatocytes / Q000201:enzymology* / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism; D008103:Liver Cirrhosis / Q000201:enzymology* / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D008288:Malaria / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D036183:Receptor, EphB2 / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D019707:Receptors, Chemokine; D036183:Receptor, EphB2