6月24日，国际著名学术期刊《血液》（Blood）在线发表了中科院上海生命科学研究院营养所王福俤研究组的科研论文“Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses”。该论文以小鼠为实验模型，通过在巨噬细胞中条件性敲除铁泵蛋白Ferroportin1（Fpn1），首次阐明了巨噬细胞Fpn1在维持机体铁稳态的重要作用，揭示了Fpn1—巨噬细胞—免疫应激间的体内网络调控机制。

机体铁稳态代谢具有非常复杂而紧密的调控体系，在正常生理状态下，约5%的铁由肠道吸收满足人体日常生理需要，95%的铁来源于巨噬细胞，巨噬细胞吞噬裂解衰老的红细胞，然后将解离出的铁离子泵回血液中被再利用（Iron Recycling）。前期研究发现，Fpn1在巨噬细胞表达并可能参与细胞铁外排过程。Fpn1突变可以引发以器官铁蓄积为主要症状的人类遗传病——血色病，晚期多伴有肝硬化、糖尿病等并发症，但Fpn1在巨噬细胞参与铁稳态代谢中的分子机制目前还不十分清楚。

王福俤研究员指导博士研究生张竹珍等用LysM-cre与F4/80-cre小鼠与Fpn1-floxed小鼠杂交，制备了两种巨噬细胞Fpn1条件性敲除小鼠模型。在正常饲料饲养时，巨噬细胞Fpn1敲除小鼠表现出轻度贫血与肝脏、脾脏及骨髓巨噬细胞轻度铁累积的复杂表型；在注射葡聚糖铁或苯肼诱导溶血性贫血的实验中，Fpn1敲除小鼠巨噬细胞中累积了更多的铁离子；在缺铁饲料饲养时，Fpn1敲除小鼠表现为更严重的贫血表型，脾脏和肝脏铁水平与对照小鼠差异加大，提示Fpn1敲除后巨噬细胞铁动员受阻，同时还提示在正常饲料饲养的Fpn1敲除小鼠，肠道铁吸收起到了一定的代偿作用。进一步实验还发现，巨噬细胞Fpn1缺失可导致小鼠炎症刺激细胞因子分泌异常，并最终证实是Fpn1外排细胞铁异常而影响了巨噬细胞免疫功能。

本论文首次在小鼠体内提供了巨噬细胞中Fpn1是具有外排铁离子以及参与免疫功能的实验证据。该研究为深入理解巨噬细胞铁稳态调控分子机制提供了坚实的实验证据，为炎症感染以及铁代谢失衡相关疾病防治提供了重要理论依据。

王福俤研究组近年来围绕巨噬细胞与铁稳态调控先后取得了一系列重要发现。该研究工作得到国家自然科学基金委、科技部“973”、中国科学院及上海市科委经费支持。

原文出处：

Blood     doi: 10.1182/blood-2011-01-330324

Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses

Zhuzhen Zhang, Fan Zhang, Peng An, Xin Guo, Yuanyuan Shen, Yunlong Tao, Qian Wu, Yuchao Zhang, Yu Yu, Bo Ning, Guangjun Nie, Mitchell D. Knutson, Gregory J. Anderson, and Fudi Wang

Systemic iron requirements are met predominantly through the recycling of iron from senescent erythrocytes by macrophages, a process in which the iron exporter ferroportin (Fpn1) is considered to be essential. Yet the role of Fpn1 in macrophage iron recycling and whether it influences innate immune responses is poorly understood in vivo. We inactivated Fpn1 in macrophages by crossing Fpn1-floxed animals with macrophage-targeted LysM-Cre or F4/80-Cre transgenic mice. Macrophage Fpn1 deletion mice were overtly normal, however, they displayed a mild anemia and iron accumulation in splenic, hepatic, and bone marrow macrophages when fed a standard diet. Iron loading was exacerbated following the administration of iron dextran or phenylhydrazine. When Fpn1LysM/LysM mice were challenged with an iron-deficient diet, they developed a more severe anemia and strikingly higher splenic iron levels than control mice, indicating significantly impaired iron mobilization from macrophages. Since immune responses can be altered by modulating iron status, we also examined the expression of pro-inflammatory cytokines. We found that expression levels of TNF-alpha and IL-6 were significantly enhanced in Fpn1LysM/LysM macrophages lacking Fpn1. These studies demonstrate that Fpn1 plays important roles in macrophage iron release in vivo and in modulating innate immune responses.