Iron metabolism in inflammation has been mostly characterized in macrophages exposed to pathogens or inflammatory conditions, mimicked by the combined action of LPS and IFN-c (M1 polarization). However, macrophages can undergo an alternative type of activation stimulated by Th2 cytokines, and acquire a role in cell growth and tissue repair control (M2 polarization). We characterized the expression of genes related to iron homeostasis in fully differentiated unpolarized (M0), M1 and M2 human macrophages. The molecular signature of the M1 macrophages showed changes in gene expression (ferroportin repression and H ferritin induction) that favour iron sequestration in the reticuloendothelial system, a hallmark of inflammatory disorders, whereas the M2 macrophages had an expression profile (ferroportin upregulation and the downregulation of H ferritin and heme oxygenase) that enhanced iron release. The conditioned media from M2 macrophages promoted cell proliferation more efficiently than those of M1 cells and the effect was blunted by iron chelation. The role of ferroportin-mediated iron release was demonstrated by the absence of differences from the media of macrophages of a patient with loss of function ferroportin mutation. The distinct regulation of iron homeostasis in M2 macrophages provides insights into their role under pathophysiological conditions. Key words: Immune system . Iron . Polarized macrophages IntroductionMacrophages play a critical role in body iron homeostasis by recovering iron from old red blood cells and returning it to the circulation for binding to transferrin, which delivers the metal to the cells that need it for various functions, thus contributing more than 80% to daily iron turnover [1][2][3].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]. Increased iron retention within inflammatory macrophages is due to increased iron uptake and decreased iron export [7], and is favoured by the induction of the iron storage protein ferritin (Ft) [8,9]. The blockade of macrophage iron release is mainly due to the interaction between the acute phase protein hepcidin and the iron exporter ferroportin (Fpn) [1][2][3], as the increase in circulating hepcidin triggered by inflammatory cytokines causes the internalization and degradation of Fpn [10], the exporter of non-heme iron [11], thus blocking iron release from macrophages.Macrophage Fpn is also negatively regulated at transcriptional and post-transcriptional levels by inflammatory mediators [12][13][14]. It is still unknown whether the inflammatory response affects the feline leukemia virus, subgroup C, receptor that exports heme from macrophages [15] and whether the heme transporter HRG1 proteins play a role in macrophage iron metabolism [16]. O...

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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.

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The transferrin receptor (TfR1), which mediates cellular iron uptake through clathrin-dependent endocytosis of iron-loaded transferrin, plays a key role in iron homeostasis. Since the number of TfR1 molecules at the cell surface is the rate-limiting step for iron entry into cells and is essential to prevent iron overload, TfR1 expression is precisely controlled at multiple levels. In this review, we have discussed the latest advances in the molecular regulation of TfR1 expression and we have considered current understanding of TfR1 function beyond its canonical role in providing iron for erythroid precursors and rapidly proliferating cells.