Interferon-γ limits the availability of iron for intramacrophage Salmonella typhimurium
Interferon-γ limits the availability of iron for intramacrophage Salmonella typhimurium
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DOI：
10.1002/eji.200738056
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发表时间：
2008-07-01
影响因子：
5.4
通讯作者：
Weiss, Guenter
中科院分区：
文献类型：
--
作者：
Nairz, Manfred;Fritsche, Gernot;Weiss, Guenter
在刺激单核吞噬细胞的效应功能中，IFN-γ在宿主防御包括沙门氏菌在内的巨噬细胞内病原体中具有关键重要性。由于IFN-γ的活性受铁的调节，并且由于足够的铁可用性对于病原体的生长是必不可少的，因此我们研究了IFN-γ对鼠伤寒沙门氏菌感染的小鼠巨噬细胞中的铁稳态和免疫功能的调节作用。在沙门氏菌感染的吞噬细胞中，IFN-γ引起铁摄取Uia转铁蛋白受体1的显著减少，并导致由铁输出体膜铁转运蛋白1的表达增强引起的铁流出增加。此外，血红素加氧酶1和铁载体捕获抗微生物肽脂质运载蛋白2的表达在细菌入侵后显著升高，IFN-γ发挥超诱导作用。这种观察到的IFN-γ的调节作用减少了感染的吞噬细胞内的细胞内铁池，从而限制了吞噬的鼠伤寒沙门氏菌对铁的获取，同时促进NO和TNF-α的产生。我们的数据表明，响应于IFN-γ的巨噬细胞铁代谢的关键途径的调节一致地旨在从细胞内沙门氏菌收回铁和增强巨噬细胞免疫应答功能。因此，这些规定符合营养免疫的原则。
In stimulating effector functions of mononuclear phagocytes, IFN-gamma is of pivotal importance in host defense against intramacrophage pathogens including salmonellae. As the activity of IFN-gamma is modulated by iron and since a sufficient availability of iron is essential for the growth of pathogens, we investigated the regulatory effects of IFN-gamma on iron homeostasis and immune function in murine macrophages infected with Salmonella typhimurium. In Salmonella -infected phagocytes, IFN-gamma caused a significant reduction of iron uptake Uia transferrin receptor 1 and resulted in an increased iron efflux caused by an enhanced expression of the iron exporter ferroportin 1. Moreover, the expression of haem oxygenase 1 and of the siderophore-capturing antimicrobial peptide lipocalin 2 was markedly elevated following bacterial invasion, with IFN-gamma exerting a super-inducing effect. This observed regulatory impact of IFN-gamma reduced the intracellular iron pools within infected phagocytes, thus restricting the acquisition of iron by engulfed Salmonella typhimurium while concomitantly promoting NO and TNF-alpha production. our data suggest that the modulation of crucial pathways of macrophage iron metabolism in response to IFN-gamma concordantly aims at withdrawing iron from intracellular Salmonella and at strengthening macrophage immune response functions. These regulations are thus consistent with the principles of nutritional immunity.