Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 164, Issue 2B, Pages 406-418Publisher
WILEY
DOI: 10.1111/j.1476-5381.2010.01120.x
Keywords
macrophages; iron; oxidative stress; infection; anaemia; chelators
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Funding
- Israel Science Foundation [141/06]
- Canadian Friends of the Hebrew University [LSHM-CT-2006-037296 Euroiron1]
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BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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. KEY RESULTS 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. CONCLUSIONS AND IMPLICATIONS 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.
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