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Iron homeostasis in host defence and inflammation

Key Points

  • Iron is an essential trace metal for nearly all microorganisms. Microorganisms devote substantial metabolic resources to obtaining adequate iron under various environmental conditions.

  • Systemic iron homeostasis in vertebrates is controlled by the interaction of the hepatic peptide hormone hepcidin with its receptor, the iron exporter ferroportin. By causing the endocytosis and proteolysis of ferroportin, hepcidin controls the major iron flows into the plasma and extracellular fluid, and regulates extracellular iron concentration.

  • Systemic iron homeostasis is markedly altered within hours of infection. Driven by interleukin-6 and other cytokines, hepcidin concentrations in the extracellular fluid increase, causing the endocytosis of ferroportin from macrophages, the sequestration of iron in macrophages and a rapid decline in extracellular iron concentrations.

  • Iron overload disorders caused by hepcidin deficiency result in immune deficits that predispose to infections with siderophilic bacteria.

  • Recent studies have provided insight into the protective roles of hypoferraemia and macrophage iron sequestration in early phases of infection with malaria parasites and siderophilic bacteria. Further studies are needed to understand the effects of these iron shifts on common extracellular infectious agents.

  • Paradoxically, the systemic hepcidin responses that may protect against extracellular microorganisms may also favour iron delivery to intracellular microorganisms that reside in macrophages. Local mechanisms that are activated by interferon-γ in macrophages — including increased expression of NRAMP1 (natural resistance-associated macrophage protein 1) and nitric oxide-stimulated production of ferroportin — may counter these potentially maladaptive systemic responses by decreasing phagosomal iron concentrations in infected macrophages.

Abstract

Iron is an essential trace element for multicellular organisms and nearly all microorganisms. Although iron is abundant in the environment, common forms of iron are minimally soluble and therefore poorly accessible to biological organisms. Microorganisms entering a mammalian host face multiple mechanisms that further restrict their ability to obtain iron and thereby limit their pathogenicity. Iron levels also modulate host defence, as iron content in macrophages regulates their cytokine production. Here, we review recent advances that highlight the role of systemic and cellular iron-regulating mechanisms in protecting hosts from infection, emphasizing aspects that are applicable to human health and disease.

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Figure 1: Iron homeostasis and its modulation by erythropoiesis and inflammation.
Figure 2: Regulation of HAMP transcription.
Figure 3: Hepcidin-induced sequestration of iron in macrophages.

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Acknowledgements

The authors acknowledge generous support from the Will Rogers Fund, which has allowed them to explore new directions in their research.

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Correspondence to Tomas Ganz.

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Competing interests

T.G and E.N. are consultants and shareholders for Merganser Biotech, a company involved in the development of minihepcidins as therapeutics. T.G. and E.N. are consultants and shareholders of Silarus Therapeutics, a company involved in the development of erythroferrone agonists and antagonists for therapeutic use.

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Glossary

β-thalassaemia

An autosomal-recessive genetic disorder in which there is a mutation in the gene encoding β-globin chains that make up haemoglobin. Thalassaemia can also be caused by mutation of the gene encoding the α-globin chain. Mutations lead to reduced globin chain synthesis, causing anaemia of variable severity. Carriers of the thalassaemia mutations are partially protected from malaria infection. This selective advantage is thought to contribute to the persistence of this potentially harmful mutation in the human genetic pool.

Siderophilic bacteria

Bacteria that become more pathogenic when iron concentrations in the blood or tissues are increased. Vibrio vulnificus and Yersinia entercolitica are the most prominent examples.

Siderophore

An organic molecule that is synthesized by microorganisms to chelate environmental iron and deliver it for microbial uptake.

Minihepcidins

Synthetic peptides that act as potent hepcidin agonists. Their design is based on the amino-terminal 7–9 amino acid sequence of hepcidin, which is modified to have greater stability, duration of action and potency by substitution of natural for unnatural amino acids and by covalent addition of a fatty or bile acid moiety.

M2 phenotype

Macrophages develop diverse phenotypic characteristics in response to signals from their tissue environment. M1 (inflammatory) macrophages develop following stimulation with Toll-like receptor ligands and interferon-γ, whereas M2 (alternatively activated) macrophages develop in the presence of interleukin-4 (IL-4) and/or IL-13. Relevant to iron metabolism, macrophages of the M2 phenotype express ferroportin and recycle iron from damaged tissues.

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Ganz, T., Nemeth, E. Iron homeostasis in host defence and inflammation. Nat Rev Immunol 15, 500–510 (2015). https://doi.org/10.1038/nri3863

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