Deficiency in the receptor tyrosine kinase EphB2 attenuates experimentally-induced liver fibrosis in mice (CAM1P.156)

Beyond the well-defined role of Eph receptor tyrosine kinases in biological processes, cell migration, adhesion, nothing is known about their implication in liver pathologies. During blood-stage rodent malaria infection, EphB2 mRNA and proteins are upregulated in the liver, a result likely driven by elevated surface expression on macrophages. This is significant for malaria pathogenesis because EphB2 -/- mice are protected from malaria-induced liver fibrosis despite having a similar liver parasite burden compared with littermate mice. This protection is correlated with a defect in inflammatory potential of hepatocytes from EphB2 -/- mice resulting in a reduction in adhesion molecules, chemokine/chemokine receptors RNA levels and infiltration of leukocytes including Kupffer cells which mediate liver fibrosis during malaria. These observations are recapitulated in the well-established carbon tetrachloride (CCL 4 ) model of liver fibrosis in which EphB2-/- CCL 4 -treated mice showed a significant reduction of liver fibrosis compared to CCL 4 -treated littermate mice. EphB2 is predominantly expressed by Kupffer cells and depletion of macrophages abrogates liver EphB2 mRNA and protein increase in malaria infected mice, as well as fibrosis. Altogether these results reinforce the critical role played by EphB2 in promoting liver inflammation and fibrosis. To our knowledge, this work is the first to reveal the potential profibrotic nature of EphB receptor tyrosine kinases in liver injury.