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Computational modeling and analysis of iron release from macrophages

Potdar AA1, Sarkar J2, Das NK3, Ghosh P3, Gratzl M2, Fox PL3, Saidel GM2. PLoS Comput Biol. 2014;10(7):e1003701.

1Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, United States of America; Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, United States of America.and

2Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, United States of America. and

3Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, United States of America.

 

Abstract

A major process of iron homeostasis in whole-body iron metabolism is the release of iron from the macrophages of the reticuloendothelial system. Macrophages recognize and phagocytose senescent or damaged erythrocytes. Then, they process the heme iron, which is returned to the circulation for reutilization by red blood cell precursors during erythropoiesis. The amount of iron released, compared to the amount shunted for storage as ferritin, is greater during  iron deficiency. A currently accepted model of iron release assumes a passive-gradient with free diffusion of intracellular labile iron (Fe2+) through ferroportin (FPN), the transporter on the plasma membrane. Outside the cell, a multi-copper ferroxidase, ceruloplasmin (Cp), oxidizes ferrous to ferric ion. Apo-transferrin (Tf), the primary carrier of soluble iron in the plasma, binds ferric ion to form mono-ferric and di-ferric transferrin. According to the passive-gradient model, the removal of ferrous ion from the site of release sustains the gradient that maintains theiron release. Subcellular localization of FPN, however, indicates that the role of FPN may be more complex. By experiments and mathematical modeling, we have investigated the detailed mechanism of iron release from macrophages focusing on the roles of the Cp, FPN and apo-Tf. The passive-gradient model is quantitatively analyzed using a mathematical model for the first time. A comparison of experimental data with model simulations shows that the passive-gradient model cannot explain macrophage iron release. However, a facilitated-transport model associated with FPN can explain the iron release mechanism. According to the facilitated-transport model, intracellular FPN carries labile iron to the macrophage membrane. Extracellular Cp accelerates the oxidation of ferrous ion bound to FPN. Apo-Tf in the extracellular environment binds to the oxidized ferrous ion, completing the release process. Facilitated-transport model can correctly predict cellular iron efflux and is essential for physiologically relevant whole-body model of iron metabolism.

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Significance Statement

Tight regulation of iron is essential to prevent iron deficiency as well as overload that can lead to diseases such as anemia and hemochromatosis. Recycling of iron by macrophages is an important process required to maintain iron homeostatsis.  From an analysis of experimental data using mathematical modeling and computer simulation, a key mechanism was revealed by which macrophages release iron.  This molecular mechanism, specifically, facilitated transport is associated with iron transport via ferroportin (FPN). The exact role of the iron transport protein, FPN in the macrophage iron efflux process is described for first time. This work has improved our understanding of the iron recycling process and overall iron metabolism. The quantitative predictive model of cellular iron efflux developed in this study is essential for correctly modeling the whole-body iron metabolism in health and disease.

 

Figure Legend:

Illustration of facilitated transport mechanism showing the transport of ferrous ion by FPN from cytosol to membrane. At the membrane ferrous-FPN is oxidized to ferric-FPN, FPN is recycled back and apo-Tf binds to ferric iron.

Source: PLoS Comput Biol 10(7): e1003701. doi:10.1371/journal.pcbi.1003701

 

 

Computational Modeling and Analysis of Iron Release from Macrophages. Global Medical Discovery