Regulatory role of iron transport in stress and ineffective erythropoiesis

摘要 我们的实验室旨在详细了解铁转运如何影响红细胞生成以及铁转运如何影响红细胞生成。 铁蛋白将铁的需求传达给肝脏。红细胞生成所需的铁是由铁转运的， 转铁蛋白转运蛋白（Tf）和红系前体细胞的铁摄取需要Tf-Fe与转铁蛋白受体结合 1（TfR1）。反过来，红系前体细胞部分通过分泌因子来调节铁代谢，例如 最近发现的erythroferrone（ERFE），它抑制激素hepcidin，一个关键的饮食抑制剂， 铁的吸收，衰老红细胞的再循环和铁储存的动员。ERFE增加， 应激（即放血的野生型小鼠）和无效红细胞生成（即β-地中海贫血 小鼠）。此外，红系前体表达铁和血红素输出蛋白，其功能仍然存在。 不清楚我们已经证明，外源性无铁转铁蛋白改善β地中海贫血患者无效的红细胞生成， 小鼠（Li等人，Nat Med，2010），导致ERFE降低、铁调素增加和相对全身铁 缺陷我们假设外源性转铁蛋白对β地中海贫血小鼠的有益作用是一种免疫抑制剂。 比坦率的铁限制的后果。具体来说，我们的初步数据表明，Tf 通过对TfR 1的作用发挥作用，通过对膜TfR 1以及铁的作用影响去核 通过降低Erfe表达间接地和通过降低可溶性TfR 1直接地代谢。此外，委员会认为， 令人惊讶的是，铁调素表达在TfR 1 +/-小鼠中没有被抑制，尽管相对缺乏铁 红细胞生成和ERFE表达增加。因此，我们假设， 外源性Tf对无效红细胞生成的影响是TfR 1表达减少或改变的结果。 TfR 1从红细胞前体的运输。在这里，我们建议详细定义Tf的变化 铁浓度、铁摄取和外排以及TfR 1在红细胞中的运输影响红细胞生成和红系细胞 hepcidin调节在建议的三个具体目标中，我们将1）评估Tf和TfR 1在以下方面的调节作用： 铁限制性和无效的红细胞生成; 2）检查TfR 1作为铁调素调节剂的意义; 阐明Tf和TfR 1对红系前体细胞和肝细胞铁外排的影响。铁 红细胞生成的转运和铁代谢的红细胞调节是在恢复期间的中心原则。 应激红细胞生成并在无效红细胞生成中失调。因此，圆满完成这些 阐明Tf和TfR 1在这些途径中的作用的研究是血液学领域非常感兴趣的， 提供了深入了解人类疾病的病理生理学，其中红细胞生成受到干扰， 目前的知识，铁代谢，并增加了新的范例，为进一步探索红细胞调节， 铁调素最后，这些研究的成功完成，涉及压力和 无效的红细胞生成（对PAS-13-031有反应）将促进使用Tf在 β-地中海贫血和可能的其他铁负荷性贫血患者。

ABSTRACT Our laboratory aims to understand in detail how iron transport influences erythropoiesis and how the erythron communicates iron requirements to the liver. Iron for erythropoiesis is transported by the iron transporter transferrin (Tf) and iron uptake by erythroid precursors requires Tf-Fe binding to transferrin receptor 1 (TfR1). In turn, erythroid precursors regulate iron metabolism in part by secreting factors, such as the recently identified erythroferrone (ERFE), which suppresses the hormone hepcidin, a key inhibitor of dietary iron absorption, recycling from senescent RBCs, and mobilization from iron stores. ERFE is increased in models of both stress (i.e. phlebotomized wild type mice) and ineffective erythropoiesis (i.e. β-thalassemic mice). Furthermore, erythroid precursors express iron and heme export proteins, the function of which remains unclear. We have shown that exogenous iron-free Tf ameliorates ineffective erythropoiesis in β-thalassemic mice (Li et al., Nat Med, 2010), resulting in decreased ERFE, increased hepcidin, and relative systemic iron deficiency. We hypothesize that the beneficial effect of exogenous Tf in β-thalassemic mice is a consequence of more than frank iron restriction. Specifically, our preliminary data suggests that Tf functions via an effect on TfR1, influencing enucleation through effects on membrane TfR1 as well as iron metabolism indirectly by decreasing Erfe expression and directly by decreasing soluble TfR1. Furthermore, surprisingly, hepcidin expression is not suppressed in TfR1+/- mice, despite relative iron deficient erythropoiesis and increased ERFE expression. Thus, we hypothesize that the beneficial effect of exogenous Tf on ineffective erythropoiesis is a consequence of reduced TfR1 expression or altered TfR1 trafficking from erythroid precursors. Here we propose to define in detail how changes in Tf concentration, iron uptake and efflux, and TfR1 trafficking in the erythron influence erythropoiesis and erythroid hepcidin regulation. In the proposed three specific aims, we will 1) assess the regulatory role of Tf and TfR1 in iron restricted and ineffective erythropoiesis; 2) examine the significance of TfR1 as a regulator of hepcidin; and 3) elucidate the effect of Tf and TfR1 on iron efflux from erythroid precursors and hepatocytes. Iron transport for erythropoiesis and erythroid regulation of iron metabolism are central tenets in recovery during stress erythropoiesis and are dysregulated in ineffective erythropoiesis. Thus, successful completion of these studies elucidating the role of Tf and TfR1 in these pathways is of great interest to the hematology field, provides insight into the pathophysiology of human diseases in which erythropoiesis is disturbed, extends current knowledge in iron metabolism, and adds new paradigms for further exploring erythroid regulation of hepcidin. Lastly, the successful completion of these studies interrogating mechanisms involved in stress and ineffective erythropoiesis (responsive to PAS-13-031) will facilitate the development of clinical trials using Tf in patients with β-thalassemia and possibly other iron-loading anemias.