Blood:揭示鐵泵蛋白Fpn1在鐵代謝中作用

6月24日，國際著名學術期刊《血液》（Blood）在線發表了中科院上海生命科學研究院營養所王福俤研究組的科研論文「Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses」。該論文以小鼠為實驗模型，通過在巨噬細胞中條件性敲除鐵泵蛋白Ferroportin1（Fpn1），首次闡明了巨噬細胞Fpn1在維持機體鐵穩態的重要作用，揭示了Fpn1—巨噬細胞—免疫應激間的體內網絡調控機制。

機體鐵穩態代謝具有非常複雜而緊密的調控體系，在正常生理狀態下，約5%的鐵由腸道吸收滿足人體日常生理需要，95%的鐵來源於巨噬細胞，巨噬細胞吞噬裂解衰老的紅細胞，然後將解離出的鐵離子泵回血液中被再利用（Iron Recycling）。前期研究發現，Fpn1在巨噬細胞表達並可能參與細胞鐵外排過程。Fpn1突變可以引發以器官鐵蓄積為主要症狀的人類遺傳病——血色病，晚期多伴有肝硬化、糖尿病等併發症，但Fpn1在巨噬細胞參與鐵穩態代謝中的分子機制目前還不十分清楚。

王福俤研究員指導博士研究生張竹珍等用LysM-cre與F4/80-cre小鼠與Fpn1-floxed小鼠雜交，製備了兩種巨噬細胞Fpn1條件性敲除小鼠模型。在正常飼料飼養時，巨噬細胞Fpn1敲除小鼠表現出輕度貧血與肝臟、脾臟及骨髓巨噬細胞輕度鐵累積的複雜表型；在注射葡聚糖鐵或苯肼誘導溶血性貧血的實驗中，Fpn1敲除小鼠巨噬細胞中累積了更多的鐵離子；在缺鐵飼料飼養時，Fpn1敲除小鼠表現為更嚴重的貧血表型，脾臟和肝臟鐵水平與對照小鼠差異加大，提示Fpn1敲除後巨噬細胞鐵動員受阻，同時還提示在正常飼料飼養的Fpn1敲除小鼠，腸道鐵吸收起到了一定的代償作用。進一步實驗還發現，巨噬細胞Fpn1缺失可導致小鼠炎症刺激細胞因子分泌異常，並最終證實是Fpn1外排細胞鐵異常而影響了巨噬細胞免疫功能。

本論文首次在小鼠體內提供了巨噬細胞中Fpn1是具有外排鐵離子以及參與免疫功能的實驗證據。該研究為深入理解巨噬細胞鐵穩態調控分子機制提供了堅實的實驗證據，為炎症感染以及鐵代謝失衡相關疾病防治提供了重要理論依據。

王福俤研究組近年來圍繞巨噬細胞與鐵穩態調控先後取得了一系列重要發現。該研究工作得到國家自然科學基金委、科技部「973」、中國科學院「百人計劃」及上海市科委經費支持。（生物谷Bioon.com）

生物谷推薦原文出處：

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.

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