from activated lymphocyte subsets, macrophages undergo adaptive responses essential for a coordinated immune response, resistance to pathogens, and tissue repair. During the last few years increasing evidence has accumulated indicating that macrophage plasticity can be viewed as a spectrum of activation status between the classic pro-inflammatory (M1) program, induced by bacterial moieties such as lipopolysaccharides and the Th1 cytokine interferon-γ, and the alternative tissue repair-prone (M2) program, originally discovered as a response to the Th2 cytokine interleukin-4, mirroring Th1/Th2 polarization. 1 It is now appreciated that M2-like functional phenotypes can also be induced by other signals, including antibody immune complexes together with lipopolysaccharides/interleukin-1, glucocorticoids, transforming growth factor beta-β, and interleukin-10. 2 Polarized macrophages differ greatly in expression of immunoregulatory genes and profoundly influence immune responses and tissue homeostasis. 3, 4 M1 macrophages are characterized by high levels of pro-inflammatory cytokines (interleukin-12, interleukin-23, tumor necrosis factor-α) and an interleukin-12high/interleukin-10low phenotype, produce reactive nitrogen and oxygen intermediates, express high levels of major histocompatibility class II and co-stimulatory molecules, and display microbicidal activity. In this context, it is relevant to recall that M1 macrophages are also characterized by marked iron sequestration properties, which contribute to the cells’ bacteriostatic effects. 5 M1 macrophages are part of polarized Th1 responses and mediate resistance to intracellular pathogens and tumors. Of note, under these activated conditions, M1 cells can also elicit tissue disruptive reactions. Conversely, M2 macrophages show increased phagocytic activity, high expression of scavenging, mannose and galactose receptors, production of ornithine and polyamines through the arginase pathway, and an interleukin-12low/interleukin-10high phenotype. In general, these cells participate in polarized Th2 responses, help in parasite clearance, dampen inflammation, promote tissue remodeling, and possess immunoregulatory functions. 6 Macrophages are also key elements linking inflammation and cancer, and tumor-associated macrophages are also characterized by an alternative-like activation phenotype. 7, 8 In addition to their role in immunity, macrophages are of central importance to body iron homeostasis, as the main iron supply for erythropoiesis derives from the iron recycled by macrophages after phagocytosis of senescent red blood cells. 9 Iron retention in the reticuloendothelial system is a well characterized response of body iron homeostasis to inflammation, as a host’s attempt to withhold iron from the invading pathogens. This may eventually restrict iron availability for erythroid precursors and may contribute toward causing the common condition of inflammation-related anemia. However, recent studies have revealed that the role of macrophages in iron homeostasis is multifaceted and more complex than previously suspected. In this issue of Haematologica, Corna and colleagues show that mouse macrophage polarization also affects iron homeostasis. 10 Similar results were reported earlier this year for human polarized macrophages, 11 indicating that differential iron management is a conserved functional property of human and murine polarized macrophages, differently from other functional aspects not conserved across species. 3 Moreover, a recent study showed that glucocorticoids polarize monocytes toward a M2 phenotype characterized by hemoglobin clearance and export …