The receptor tyrosine kinase EphB2 promotes hepatic fibrosis in mice.

Abstract

UNLABELLED 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.

DOI: 10.1002/hep.27792

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@article{Mimche2015TheRT, title={The receptor tyrosine kinase EphB2 promotes hepatic fibrosis in mice.}, author={Patrice Nsangou Mimche and Lauren M. Brady and Christian F Bray and Choon Meng Lee and Manoj Thapa and Thayer P. King and Kendra M Quicke and Courtney D. McDermott and Sylvie M. Mimche and Arash Grakoui and E. Timothy Morgan and Tracey J Lamb}, journal={Hepatology}, year={2015}, volume={62 3}, pages={900-14} }