The receptor tyrosine kinase EphB2 promotes hepatic fibrosis in mice.
The receptor tyrosine kinase EphB2 promotes hepatic fibrosis in mice.
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DOI：
10.1002/hep.27792
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发表时间：
2015-09
期刊：
影响因子：
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通讯作者：
Lamb TJ
中科院分区：
文献类型：
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作者：
Mimche PN;Brady LM;Bray CF;Lee CM;Thapa M;King TP;Quicke K;McDermott CD;Mimche SM;Grakoui A;Morgan ET;Lamb TJ
除了 Eph 受体酪氨酸激酶在发育过程、细胞运动、细胞运输/粘附和癌症中明确的作用外，人们对它们在肝脏病理学中的参与一无所知。在血液阶段啮齿动物疟疾感染期间，我们发现肝脏中 EphB2 转录本和蛋白质上调，这一结果可能是由包括巨噬细胞在内的免疫细胞表面表达升高所致。这对于疟疾发病机制具有重要意义，因为尽管与同窝对照小鼠相比，EphB2−/− 小鼠具有相似的肝脏寄生虫负担，但它们免受疟疾诱导的肝纤维化的影响。这种保护与 EphB2−/− 小鼠肝细胞炎症潜力的缺陷相关，导致粘附分子、趋化因子/趋化因子受体 RNA 水平降低以及白细胞浸润，包括巨噬细胞/枯否细胞，在啮齿动物疟疾感染期间介导肝纤维化。这些观察结果在成熟的四氯化碳 (CCL4) 肝纤维化模型中得到了概括，其中与 CCL4 处理的同窝小鼠相比，EphB2−/− CCL4 处理的小鼠表现出肝纤维化显着减少。氯膦酸盐脂质体消耗巨噬细胞会消除感染疟疾的小鼠肝脏 EphB2 mRNA 和蛋白质的上调和纤维化。结论：在啮齿动物疟疾期间，EphB2 表达促进疟疾相关的肝纤维化。据我们所知，我们的数据首次揭示了受体酪氨酸激酶 EphB 家族在肝纤维化或疟疾感染发病机制中的影响。
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.