6月24日,，國際著名學(xué)術(shù)期刊《血液》（Blood）在線發(fā)表了中科院上海生命科學(xué)研究院營養(yǎng)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?zāi)Ｐ停ㄟ^在巨噬細(xì)胞中條件性敲除鐵泵蛋白Ferroportin1（Fpn1）,，首次闡明了巨噬細(xì)胞Fpn1在維持機(jī)體鐵穩(wěn)態(tài)的重要作用,，揭示了Fpn1—巨噬細(xì)胞—免疫應(yīng)激間的體內(nèi)網(wǎng)絡(luò)調(diào)控機(jī)制。
機(jī)體鐵穩(wěn)態(tài)代謝具有非常復(fù)雜而緊密的調(diào)控體系,，在正常生理狀態(tài)下,，約5%的鐵由腸道吸收滿足人體日常生理需要，95%的鐵來源于巨噬細(xì)胞,，巨噬細(xì)胞吞噬裂解衰老的紅細(xì)胞,，然后將解離出的鐵離子泵回血液中被再利用（Iron Recycling）。前期研究發(fā)現(xiàn),，F(xiàn)pn1在巨噬細(xì)胞表達(dá)并可能參與細(xì)胞鐵外排過程,。Fpn1突變可以引發(fā)以器官鐵蓄積為主要癥狀的人類遺傳病——血色病，晚期多伴有肝硬化,、糖尿病等并發(fā)癥,，但Fpn1在巨噬細(xì)胞參與鐵穩(wěn)態(tài)代謝中的分子機(jī)制目前還不十分清楚。
王福俤研究員指導(dǎo)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,，制備了兩種巨噬細(xì)胞Fpn1條件性敲除小鼠模型,。在正常飼料飼養(yǎng)時,，巨噬細(xì)胞Fpn1敲除小鼠表現(xiàn)出輕度貧血與肝臟、脾臟及骨髓巨噬細(xì)胞輕度鐵累積的復(fù)雜表型,；在注射葡聚糖鐵或苯肼誘導(dǎo)溶血性貧血的實驗中,，F(xiàn)pn1敲除小鼠巨噬細(xì)胞中累積了更多的鐵離子；在缺鐵飼料飼養(yǎng)時,，F(xiàn)pn1敲除小鼠表現(xiàn)為更嚴(yán)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敲除后巨噬細(xì)胞鐵動員受阻,，同時還提示在正常飼料飼養(yǎng)的Fpn1敲除小鼠,，腸道鐵吸收起到了一定的代償作用。進(jìn)一步實驗還發(fā)現(xiàn),，巨噬細(xì)胞Fpn1缺失可導(dǎo)致小鼠炎癥刺激細(xì)胞因子分泌異常,，并最終證實是Fpn1外排細(xì)胞鐵異常而影響了巨噬細(xì)胞免疫功能。
本論文首次在小鼠體內(nèi)提供了巨噬細(xì)胞中Fpn1是具有外排鐵離子以及參與免疫功能的實驗證據(jù),。該研究為深入理解巨噬細(xì)胞鐵穩(wěn)態(tài)調(diào)控分子機(jī)制提供了堅實的實驗證據(jù),，為炎癥感染以及鐵代謝失衡相關(guān)疾病防治提供了重要理論依據(jù)。
王福俤研究組近年來圍繞巨噬細(xì)胞與鐵穩(wěn)態(tài)調(diào)控先后取得了一系列重要發(fā)現(xiàn),。該研究工作得到國家自然科學(xué)基金委,、科技部“973”、中國科學(xué)院“百人計劃”及上海市科委經(jīng)費(fèi)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.
