Lipocalin 2 alleviates iron toxicity by facilitating hypoferremia of inflammation and limiting catalytic iron generation.
Lipocalin 2 alleviates iron toxicity by facilitating hypoferremia of inflammation and limiting catalytic iron generation.
复制标题
Lipocalin 2 通过促进炎症低铁血症和限制催化铁生成来减轻铁毒性。
DOI：
10.1007/s10534-016-9925-5
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Vijay-Kumar,Matam
中科院分区：
文献类型：
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作者：
Xiao,Xia;Yeoh,BengSan;Saha,Piu;Olvera,RodrigoAguilera;Singh,Vishal;Vijay-Kumar,Matam
铁是几乎所有需氧生物必需的过渡金属离子，但它的失调（铁超载或贫血）是许多病理状况的先兆。因此，铁的体内平衡受到严格调节，以防止催化铁（CI）的产生，从而破坏细胞生物分子。在这项研究中，我们利用Lcn2敲除（KO）小鼠及其WT幼崽，研究了铁结合/运输先天免疫蛋白lipocalin 2 （Lcn2,akasiderocalin）在铁和CI稳态中的作用。系统或通过饮食摄入给铁显著上调了WT小鼠血清、尿液、粪便和肝脏中的Lcn2。然而，同样处理的Lcn2KO小鼠表现出升高的CI，增强的脂质过氧化和其他器官损伤标志物指标，这表明Lcn2反应可能对铁诱导的毒性具有保护作用。本研究还发现，在右旋糖酐硫酸钠（DSS）诱导的小鼠结肠炎模型中，血清Lcn2与CI呈负相关。dss治疗的Lcn2KO小鼠无法引起急性结肠炎的低铁血症反应，暗示Lcn2参与炎症期间的铁稳态。通过骨髓嵌合体，我们进一步发现来自免疫和非免疫细胞的Lcn2参与了CI调节。值得注意的是，外源性rec-Lcn2补充抑制了Lcn2KO血清和尿液中的CI水平。总之，我们的研究结果表明，Lcn2可能促进低铁血症，抑制CI的产生，并防止铁介导的不良反应。
Iron is an essential transition metal ion for virtually all aerobic organisms, yet its dysregulation (iron overload or anemia) is a harbinger of many pathologic conditions. Hence, iron homeostasis is tightly regulated to prevent the generation of catalytic iron (CI) which can damage cellular biomolecules. In this study, we investigated the role of iron-binding/trafficking innate immune protein, lipocalin 2 (Lcn2,akasiderocalin) on iron and CI homeostasis using Lcn2 knockout (KO) mice and their WT littermates. Administration of iron either systemically or via dietary intake strikingly upregulated Lcn2 in the serum, urine, feces, and liver of WT mice. However, similarly-treated Lcn2KO mice displayed elevated CI, augmented lipid peroxidation and other indices of organ damage markers, implicating that Lcn2 responses may be protective against iron-induced toxicity. Herein, we also show a negative association between serum Lcn2 and CI in the murine model of dextran sodium sulfate (DSS)-induced colitis. The inability of DSS-treated Lcn2KO mice to elicit hypoferremic response to acute colitis, implicates the involvement of Lcn2 in iron homeostasis during inflammation. Using bone marrow chimeras, we further show that Lcn2 derived from both immune and non-immune cells participates in CI regulation. Remarkably, exogenous rec-Lcn2 supplementation suppressed CI levels in Lcn2KO serum and urine. Collectively, our results suggest that Lcn2 may facilitate hypoferremia, suppress CI generation and prevent iron-mediated adverse effects.