Cell-autonomous and systemic context-dependent functions of iron regulatory protein 2 in mammalian iron metabolism
Cell-autonomous and systemic context-dependent functions of iron regulatory protein 2 in mammalian iron metabolism
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DOI：
10.1182/blood-2008-05-155093
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发表时间：
2009-01-15
期刊：
影响因子：
20.3
通讯作者：
Galy, Bruno
中科院分区：
文献类型：
--
作者：
Ferring-Appel, Dunja;Hentze, Matthias W.;Galy, Bruno
总铁调节蛋白2（IRP 2）缺乏和组成性铁调节蛋白2（IRP 2）缺乏的小鼠表现出小红细胞症和体内铁分布改变，十二指肠和肝脏铁负荷和脾巨噬细胞铁水平降低。为了探索IRP 2的细胞自主和系统环境依赖性功能，并评估局部IRP 2缺乏的系统后果，我们应用Cre/Lox技术分别特异性消融肠细胞、肝细胞或巨噬细胞中的IRP 2。这项研究表明，肝脏和十二指肠表现的系统性IRP 2的缺陷在很大程度上解释了IRP 2的细胞自主功能。相比之下，来自其他IRP 2充足小鼠的IRP 2缺陷型巨噬细胞不显示来自全身性IRP 2缺陷型动物的巨噬细胞的异常，表明这些异常是由其他细胞类型中的IRP 2破坏引起的。肠细胞、肝细胞或巨噬细胞特异性IRP 2缺陷的小鼠显示正常的红细胞和血浆铁参数，支持IRP 2缺陷小鼠的小红细胞增多可能反映了造血的内在缺陷的观点。这项工作定义了IRP 2在确定关键的身体铁参数，如器官铁负荷和红细胞生成中的各自作用。（血。2009; 113：679-687）
Mice with total and constitutive iron regulatory protein 2 (IRP2) deficiency exhibit microcytosis and altered body iron distribution with duodenal and hepatic iron loading and decreased iron levels in splenic macrophages. To explore cell-autonomous and systemic context-dependent functions of IRP2 and to assess the systemic consequences of local IRP2 deficiency, we applied Cre/Lox technology to specifically ablate IRP2 in enterocytes, hepatocytes, or macrophages, respectively. This study reveals that the hepatic and duodenal manifestations of systemic IRP2 deficiency are largely explained by cell-autonomous functions of IRP2. By contrast, IRP2-deficient macrophages from otherwise IRP2-sufficient mice do not display the abnormalities of macrophages from systemically IRP2-deficient animals, suggesting that these result from IRP2 disruption in other cell type(s). Mice with enterocyte-, hepatocyte-, or macrophage- specific IRP2 deficiency display normal red blood cell and plasma iron parameters, supporting the notion that the microcytosis in IRP2-deficient mice likely reflects an intrinsic defect in hematopoiesis. This work defines the respective roles of IRP2 in the determination of critical body iron parameters such as organ iron loading and erythropoiesis. (Blood. 2009; 113: 679-687)