Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond Safra Campus at Givat Ram, Jerusalem, Israel.
Br J Pharmacol. 2011 Sep;164(2b):406-18. doi: 10.1111/j.1476-5381.2010.01120.x.
Systemic iron deficiency concomitant with macrophage iron retention is characteristic of iron-refractory anaemias associated with chronic disease. The systemic misdistribution of iron, which is further exacerbated by parenteral iron supplementation, is mainly attributable to iron retention exerted on resident macrophages by hepcidin-mediated down-regulation of the iron exporter ferroportin. We aimed at developing an experimental macrophage-based cell model that recapitulates pathophysiological features of iron misdistribution found in chronic disorders and use it as a screening platform for identifying agents with the potential for relocating the accumulated metal and restoring affected functions.
A raw macrophage subline was selected as cell model of iron retention based on their capacity to take up polymeric iron or aged erythrocytes excessively, resulting in a demonstrable increase of cell labile iron pools and oxidative damage that are aggravated by hepcidin.
This model provided a three-stage high throughput screening platform for identifying agents with the combined ability to: (i) scavenge cell iron and thereby rescue macrophage cells damaged by iron-overload; (ii) bypass the ferroportin blockade by conveying the scavenged iron to other iron-starved cells in co-culture via transferrin but (iii) without promoting utilization of the scavenged iron by intracellular pathogens. As test agents we used chelators in clinical practice and found the oral chelator deferiprone fulfilled essentially all of the three criteria.
We provide a proof of principle for conservative iron relocation as complementary therapeutic approach for correcting the misdistribution of iron associated with chronic disease and exacerbated by parenteral iron supplementation.
伴有巨噬细胞铁蓄积的系统性铁缺乏是与慢性疾病相关的铁难治性贫血的特征。铁在全身的分布不均，由于铁蛋白介导的铁输出蛋白 Ferroportin 的下调导致铁蓄积进一步加剧，这主要归因于铁在驻留巨噬细胞中的蓄积。我们旨在开发一种基于实验性巨噬细胞的细胞模型，该模型再现了慢性疾病中发现的铁分布异常的病理生理特征，并将其用作筛选平台，以鉴定具有重新定位蓄积金属和恢复受影响功能潜力的药物。
选择原始巨噬细胞亚系作为铁蓄积的细胞模型，基于其摄取聚合铁或衰老红细胞的能力，导致细胞不稳定铁池和氧化损伤显著增加，铁蛋白进一步加剧了这种情况。
该模型提供了一个三阶段高通量筛选平台，用于鉴定具有以下联合能力的药物：（i）清除细胞铁，从而挽救因铁过载而受损的巨噬细胞；（ii）通过转铁蛋白将清除的铁输送到共培养中的其他缺铁细胞，从而绕过 Ferroportin 阻断，但（iii）不促进细胞内病原体利用清除的铁。作为测试药物，我们使用了临床实践中的螯合剂，并发现口服螯合剂地拉罗司基本上满足了所有三个标准。
我们提供了保守性铁再定位作为纠正与慢性疾病相关的铁分布异常并减轻铁蛋白介导的铁蛋白补充治疗的补充治疗方法的原理证明。
