Iron at the interface of immunity and infection

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.

Keywords: anemia of chronic disease; bacteria; hepcidin; interferon; iron; macrophage; nitric oxide.

FIGURE 1

Iron homeostasis in differently regulated depending on the primary localization of the pathogen. During an inflammatory process cytokines and bacterial products can induce the formation of the master regulator of iron homeostasis, hepcidin, in the liver. (A) In case of infection with extracellular bacteria hepatocyte derived hepcidin targets ferroportin (FP1) on the cell surface and results in its degradation thereby reducing macrophage iron agrees. This effect is further supported by minute amounts of hepcidin produced by macrophages in response to interleukin-6 (IL-6) and by the action of interferon-gamma (IFN-γ) which inhibits ferroportin expression transcriptionally. This results in systemic hypoferremia and reduced iron availability for extracellular bacteria whereas the increased intracellular amounts of iron in the cell are incorporated into ferritin, the expression of which is induced by iron and cytokines, such as tumor necrosis factor-alpha (TNF-α), IL-1β, or IL-6. (B) While in case of an infection with intracellular bacteria hepcidin also exerts negative effects on ferroportin expression posttranslationally, this mechanisms appears to be outcompeted by massive induction of ferroportin transcription which can be traced back to activation of inducible nitric oxide synthase (iNOS) with subsequent nitric oxide (NO) formation and activation of the transcription factor Nrf2 which massively stimulate ferroportin transcription leading in summary to stimulation of iron export and reduction of intracellular iron levels. In addition, microbes residing in the phagolysome are further deprived from iron via the action of Nramp1 which pumps the metal into the cytoplasm and subsequently out of the cells by the action of ferroportin. In addition, due to the negative regulatory effect of iron on innate immune effector function and specifically IFN-γ activity, the reduction of intracellular iron levels results in stimulation of anti-microbial immune effector pathways, such as iNOS, TNF-α, or IL-12 formation which together with the reduction of cellular iron availability help to control infections with intracellular microbes.