The receptor tyrosine kinase EphB2 promotes hepatic fibrosis in mice

Abstract

Beyond the well-defined role of the Eph 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 upregulated 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, chemokines/chemokines receptors 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 (CCL4) model of liver fibrosis in which EphB2−/− CCL4-treated mice showed a significant reduction of liver fibrosis compared to CCL4-treated littermate mice. Depletion of macrophages by clodronate-liposome abrogates liver EphB2 mRNA and proteins up-regulation and fibrosis in malaria-infected mice. Conclusion: During rodent malaria, EphB2 expression promotes malaria-associated liver fibrosis. To our knowledge, our data is the first to reveal the implication of the EphB family of receptor tyrosine kinases in liver fibrosis or in the pathogenesis of malaria infection.

Blood-Stage Plasmodium Berghei ANKA Infection Promotes Hepatic Fibrosis by Enhancing Hedgehog Signaling in Mice

“…1). In line with our findings, it has been reported that inflammatory macrophages containing hemozoin in livers of malaria patients are involved in inducing liver fibrosis [35,59,60]. Therefore, these complicated liver responses against PbA infection, including iRBC sequestration, hypoxia, increased apoptotic hepatocytes, and activation of HSC and Kupffer cells, may aggravate liver injury and fibrosis during blood stage malaria.…”

Multi-omics Integrative Analysis of Acute and Relapsing Malaria in a Non-Human Primate Model ofP. vivaxinfection

“…The total number of leukocytes in the periphery was lower during acute infection and a large proportion of circulating cells displayed a memory phenotype (Figure 2A-B). This may have occurred due to trafficking to, and retention in, lymphoid organs and may be a significant feature of acute infection as repeatedly demonstrated in the lung and liver during mouse models of Plasmodium infection (Lagasse et al, 2016; Mimche et al, 2015). Indeed, this idea is consistent with cytokine levels in PB that generally increased at acute infection compared to baseline, demonstrating an elevated response (Figure 3C).…”

Non-coding RNA-mediated epigenetic regulation of liver fibrosis

“…Various inflammatory and fibrogenic pathways contribute to the activation of HSCs [5,6]. There is increasing evidence for regulatory roles of non-coding RNAs (ncRNAs) during liver fibrosis development and in response to stress and environmental stimuli [7,8].…”