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Author Notes:

Tracey J Lamb, Division of Infectious Diseases, Department of Pediatrics, Emory University School of Medicine and Emory Children's Centre, 2015 Uppergate Drive, Atlanta, Georgia 30322, USA. Telephone: +1-404-712-7883; Fax number: +1-404-727-9223; tracey.j.lamb@emory.edu.

PNM conceived the design of the experiments, performed the experiments, analyzed the data and wrote the manuscript; LMB, CFB, MT, CDM, TPK, SM, KQ and CL performed the experiments; EM and AG contributed reagents and intellectual input; TJL conceived the design of the experiments, analyzed the data and wrote the manuscript.

We thank Professor Jonathan Gibbins, University of Reading, UK for providing EphB2−/− animals; and the staff of the Division of Animal Resources for excellent animal husbandry.

We also thank Mr Aaron Rae of the Emory Pediatric Flow Cytometry Core for cell sorting; Miss Katie Casper in the Emory Pediatric Immunology Core for assistance with qPCR analysis and primers designed; Miss Deborah E. Martison and Mr Neil Anthony in the Emory University Integrated Cellular Imaging Core for assistance with microscopy.

Authors had no conflicts of interest to disclose.

Subjects:

Research Funding:

TJL is supported by National Institute for Neurological Disorders and Strokes (1R21NS085382-01A1); Children's Healthcare of Atlanta; the Royal Societ;y and Emory Egleston Children's Research Centre.

MT is supported by the NRSA training grant T32 (2T32AI70081-06AI, FY2013-2014) and F32 Fellowship grant (1F32DK101163-01, FY2014-2015).

AG is supported in part by EVC/CFAR Immunology Core P30 AI050409; Yerkes Research Center Base Grant RR-0016;, and Public Health Service AI070101.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Gastroenterology & Hepatology
  • EXPERIMENTAL CEREBRAL MALARIA
  • LIVER FIBROSIS
  • MIGRATION
  • CELLS
  • DIFFERENTIATION
  • INVOLVEMENT
  • ACTIVATION
  • EXPRESSION
  • REGULATORS
  • REGRESSION

The receptor tyrosine kinase EphB2 promotes hepatic fibrosis in mice

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Journal Title:

Hepatology

Volume:

Volume 62, Number 3

Publisher:

, Pages 900-914

Type of Work:

Article | Post-print: After Peer Review

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. Conclusion: 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.

Copyright information:

© 2015 by the American Association for the Study of Liver Diseases.

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