Abstract
Both, mammalian cells and microbes have an essential need for iron, which is required for many metabolic processes and for microbial pathogenicity. In addition, cross-regulatory interactions between iron homeostasis and immune function are evident. Cytokines and the acute phase protein hepcidin affect iron homeostasis leading to the retention of the metal within macrophages and hypoferremia. This is considered to result from a defense mechanism of the body to limit the availability of iron for extracellular pathogens while on the other hand the reduction of circulating iron results in the development of anemia of inflammation. Opposite, iron and the erythropoiesis inducing hormone erythropoietin affect innate immune responses by influencing interferon-gamma (IFN-γ) mediated (iron) or NF-kB inducible (erythropoietin) immune effector pathways in macrophages. Thus, macrophages loaded with iron lose their ability to kill intracellular pathogens via IFN-γ mediated effector pathways such as nitric oxide (NO) formation. Accordingly, macrophages invaded by the intracellular bacterium Salmonella enterica serovar Typhimurium increase the expression of the iron export protein ferroportin thereby reducing the availability of iron for intramacrophage bacteria while on the other side strengthening anti-microbial macrophage effector pathways via increased formation of NO or TNF-α. In addition, certain innate resistance genes such as natural resistance associated macrophage protein function (Nramp1) or lipocalin-2 exert part of their antimicrobial activity by controlling host and/or microbial iron homeostasis. Consequently, pharmacological or dietary modification of cellular iron trafficking enhances host resistance to intracellular pathogens but may increase susceptibility to microbes in the extracellular compartment and vice versa. Thus, the control over iron homeostasis is a central battlefield in host–pathogen interplay influencing the course of an infectious disease in favor of either the mammalian host or the pathogenic invader.
Highlights
The control over iron homeostasis is decisive in host–pathogen interaction (Schaible and Kaufmann, 2004; Nairz et al, 2010; Cassat and Skaar, 2013)
This is due to the fact that iron is central for several metabolic processes for both, prokaryotic and eukaryotic cells that the metal affects microbial proliferation and pathogenicity and in addition significantly impacts on immune cell plasticity and innate immune responses
An increased expression of Lcn2 by macrophages along with reduced intramacrophage iron content and impaired bone morphogenetic signaling may be largely responsible for the reduced susceptibility of Hfe−/− mice, a model for hereditary hemochromatosis, against infection with the intracellular bacteria Salmonella and Mycobacteria (Olakanmi et al, 2007; Corradini et al, 2009; Nairz et al, 2009b), which may be a reason of the high penetrance of this genes in people of Northern and Western European origin (Pietrangelo, 2004)
Summary
The control over iron homeostasis is decisive in host–pathogen interaction (Schaible and Kaufmann, 2004; Nairz et al, 2010; Cassat and Skaar, 2013). This leads to a reduced availability of iron for intracellular bacteria along with an activation of anti-microbial immune effector mechanisms due to counter-balancing the negative regulatory effects of iron on IFN-γ inducible immune pathways (Oexle et al, 2003; Nairz et al, 2007; Weiss and Schett, 2013).
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