A precious metal: Iron, an essential nutrient for all cells

Abstract

Iron is an important cofactor required for a number of essential cell functions and hence is a vital nutrient. However, iron can also be dangerous as a catalyst of free radical reactions. Accordingly, intracellular iron homeostasis and body iron balance are tightly regulated. In this review, we presented an overview of the remarkable new insights that over the last years have been gained into the multifaceted and sophisticated molecular mechanisms controlling iron acquisition, storage and release. We also reviewed the data about nutrition-related abnormalities of iron metabolism, such as iron overload and deficiency. Finally, we discussed how pathogenic microorganisms and host cells compete for iron, a battle whose outcome has a relevant role in infectious disease.

Differential regulation of iron homeostasis during human macrophage polarized activation

“…Given the high iron requirement of many species of bacteria, it is thought that the retention of iron in reticuloendothelial cells under inflammatory conditions represents an antibacterial response [4], as also recently indicated by the finding that bacterial stimulation of macrophages triggered a TLR4-dependent reduction in Fpn [39]. This defence mechanism directed against extracellular microrganisms could however facilitate the growth of intracellular bacteria [45], so that macrophages infected by pathogens (with the help of IFN-g [46]) activate mechanisms aimed at restricting iron availability to bacteria [47,48].…”

“…Ferroportin-mediated iron release affects the capacity of conditioned media to sustain cell growth In order to gain insight into the biological implications of the different iron release and storage capacity of the M1 and M2 macrophage populations, we hypothesized that (in vivo) the iron released by polarized macrophages could affect the proliferation of cells present in the tissue microenvironment, because iron is an essential cofactor for DNA synthesis [4]. In line with this, the addition of small (micromolar range) amounts of iron to the culture medium dose-dependently increased cell proliferation in the RCC10 renal carcinoma cell line (Fig.…”

“…Iron retention in the reticuloendothelial system is the main response of body iron homeostasis to inflammation and is regarded as a host's attempt to withhold iron from the invading pathogens [4]. This restricts iron availability for erythroid progenitor cells and may contribute toward causing the common condition of inflammation-related anaemia [1,5,6].…”

“…However, we also found a considerable difference in Fpn mRNA level between M1 and M2 macrophages. Fpn expression is also subject to transcriptional control [4,42], and decreased Fpn mRNA levels have previously been found under conditions of LPS-induced inflammation [12,39]. As Fpn is also post-transcriptionally regulated by the IRE/IRP system (see [30] for recent review), our finding of a less marked difference in Fpn protein levels between M1 and M2 macrophages than the difference in the corresponding mRNA at all the time points examined indicates that the Fpn gene is actively transcribed in M2 macrophages and that the impaired translation of Fpn mRNA due to increased IRP2-binding activity is not sufficient to abolish the increase in protein levels.…”

“…Our cell growth experiments in the presence of conditioned media with or without iron chelator showed that the high level of iron release was important in sustaining cell proliferation of both tumoural and non-tumoural cell lines. The use of conditioned media of polarized cells obtained from a patient with an inactivating mutation resulting from a defect of Fpn trafficking to the cell surface that prevents iron export [34] further indicates the role of Fpnmediated iron release in this setting.Given the high iron requirement of many species of bacteria, it is thought that the retention of iron in reticuloendothelial cells under inflammatory conditions represents an antibacterial response [4], as also recently indicated by the finding that bacterial stimulation of macrophages triggered a TLR4-dependent reduction in Fpn [39]. This defence mechanism directed against extracellular microrganisms could however facilitate the growth of intracellular bacteria [45], so that macrophages infected by pathogens (with the help of ) activate mechanisms aimed at restricting iron availability to bacteria [47,48].…”