Iron homeostasis in host defence and inflammation

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.