Lipocalin 2 deficiency dysregulates iron homeostasis and exacerbates endotoxin-induced sepsis.
Lipocalin 2 deficiency dysregulates iron homeostasis and exacerbates endotoxin-induced sepsis.
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DOI：
10.4049/jimmunol.1200892
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发表时间：
2012-08-15
期刊：
影响因子：
--
通讯作者：
Vijay-Kumar M
中科院分区：
文献类型：
--
作者：
Srinivasan G;Aitken JD;Zhang B;Carvalho FA;Chassaing B;Shashidharamurthy R;Borregaard N;Jones DP;Gewirtz AT;Vijay-Kumar M
包括败血症在内的各种炎症状态都与低铁血症有关，低铁血症限制了病原体对铁的利用并减少了铁介导的氧化应激。脂质运载蛋白 2（铁运载蛋白，24p3）在铁转运中发挥核心作用。因此，Lipocalin 2 缺陷小鼠 (Lcn2KO) 表现出细胞内不稳定铁含量升高。在这里，我们报告在 24 小时内，LPS 诱导 WT 小鼠全身性 Lcn2 增加 150 倍。相对于 WT 同窝小鼠，Lcn2KO 小鼠对内毒素血症明显更敏感，表现出器官损伤指数升高（转氨酶血症，LDH）和死亡率增加。这种加剧的内毒素血症与 caspase 3 裂解的大幅增加以及随之而来的免疫细胞凋亡的增加有关。此外，来自 Lcn2KO 小鼠的细胞对离体 LPS 高度敏感，表现出细胞因子分泌增加。此外，尽管肝脏铁调素表达正常，但 Lcn2KO 小鼠表现出延迟性 LPS 诱导的低铁血症，并且肝脏和血浆中组织氧化还原状态指标半胱氨酸和谷胱甘肽水平降低。 Desferroxamine 是一种铁螯合剂，可显着保护 Lcn2KO 小鼠免受 LPS 诱导的毒性（包括死亡），表明 Lcn2 可能通过调节铁稳态而在体内充当抗氧化剂。因此，Lcn2 介导的不稳定铁调节可以保护宿主免受脓毒症的侵害。 Lcn2 尺寸小、结构简单，可能使其成为脓毒症的可部署治疗方法。
Various states of inflammation, including sepsis, are associated with hypoferremia, which limits iron availability to pathogens and reduces iron-mediated oxidative stress. Lipocalin 2 (siderocalin, 24p3) plays a central role in iron transport. Accordingly, Lipocalin 2-deficient mice (Lcn2KO) exhibit elevated intracellular labile iron. Here we report that LPS-induced systemic Lcn2 by 150 fold in WT mice at 24h. Relative to WT littermates, Lcn2KO mice were markedly more sensitive to endotoxemia, exhibiting elevated indices of organ damage (transaminasaemia, LDH) and increased mortality. Such exacerbated endotoxemia was associated with substantially increased caspase 3 cleavage and concomitantly elevated immune cell apoptosis. Further, cells from Lcn2KO mice were hyperresponsive to LPS ex vivo exhibiting elevated cytokine secretion. In addition, Lcn2KO mice exhibited delayed LPS-induced hypoferremia despite normal hepatic hepcidin expression and display decreased levels of the tissue redox state indicators cysteine and glutathione in liver and plasma. Desferroxamine, an iron chelator, significantly protects Lcn2KO mice from LPS-induced toxicity, including mortality, suggesting that Lcn2 may act as an antioxidant in vivo by regulating iron homeostasis. Thus, Lcn2-mediated regulation of labile iron protects the host against sepsis. Its small size and simple structure may make Lcn2 as a deployable treatment for sepsis.
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影响因子：
4.3
作者：
Iyer SS;Torres-Gonzalez E;Neujahr DC;Kwon M;Brigham KL;Jones DP;Mora AL;Rojas M
通讯作者：
Rojas M
影响因子：
3.5
作者：
Borregaard, Niels;Cowland, Jack B.
通讯作者：
Cowland, Jack B.
DOI：
10.1073/pnas.0510847103
发表时间：
2006-02-07
影响因子：
11.1
作者：
Berger, T;Togawa, A;Mak, TW
通讯作者：
Mak, TW
影响因子：
16
作者：
Goetz, DH;Holmes, MA;Strong, RK
通讯作者：
Strong, RK
影响因子：
11.8
作者：
Barcia, AM;Harris, HW
通讯作者：
Harris, HW