Iron Limitation as an Innate Immune Defense
In addition to mitigating toxicity associated with hypo- or hyperferremia, regulation of iron distribution serves as an innate immune mechanism against invading pathogens. Even in the absence of infection, several facets of human iron metabolism ensure that iron is scarcely accessible to pathogenic microorganisms. First, the majority of iron in humans is sequestered intracellularly, complexed within hemoglobin inside erythrocytes. Some pathogens have therefore evolved mechanisms to liberate hemoglobin by lysing erythrocytes to ultimately extract iron from heme. However, hemolytic pathogens must subsequently compete with haptoglobin and hemopexin, host glycoproteins that scavenge liberated hemoglobin and heme, respectively (Figure 1D). A second factor limiting the availability of iron to invading pathogens is the paucity of free extracellular iron. Extracellular iron is bound with high affinity by transferrin, which in healthy individuals is typically less than 50% saturated with iron. When transferrin-binding capacity is exceeded, iron can also be chelated with lower affinity by a number of molecules in plasma including albumin, citrate, and amino acids (Nathan et al., 2003).
During infection, additional fortification of iron-withholding defense occurs (Figure 2). The hypoferremia of infection was documented in seminal studies by Cartwright et al. in the 1940s, who noted a precipitous drop in plasma iron levels upon intramuscular inoculation of canines with Staphylococcus aureus. A similar hypoferremic response was noted upon intravenous injection with sterile turpentine, suggesting that inflammation, rather than a specific microbial product, was responsible for declining plasma iron levels (Cartwright et al., 1946). Since these initial observations, much has been learned regarding the importance of iron withholding to the outcome of host-pathogen interactions.
With the oxygenation of the Earth’s atmosphere over 2 billion years ago, abundant soluble Fe2+ was oxidized to insoluble Fe3+, making bioavailable iron much more scarce.3 At the same time, iron became potentially more toxic since the redox cycling of iron in the presence of oxygen and hydrogen peroxide catalyzes the production of free radicals in the Fenton reaction that can damage DNA, protein, and lipids.4Humans and other organisms therefore evolved specialized proteins and tightly regulated homeostatic mechanisms for the uptake, transport, storage, and export of iron to provide adequate iron for essential biologic process, but to limit the toxicity of iron excess.
Brain iron loading impairs DNA methylation and alters GABAergic function in mice.
The term “hemochromatosis,” introduced by von Recklinghausen at the end of the 19th century, refers to the clinical disorder that results from excess of total body iron and organ failure due to iron toxicity. The disease manifestations include cirrhosis, diabetes mellitus, hypogonadism and other endocrinopathies, cardiomyopathy, arthropathy, skin pigmentation, and, in cirrhotic patients, increased susceptibility to liver cancer.