Hepcidin at the Nexus of Infection and Anemia

Humans have two main reasons for needing to control the amount and distribution of iron in the body. First, iron is used in fundamental physiological processes, including carrying oxygen, generating energy from oxygen, and in utilizing the energy for activities such as macromolecular synthesis and DNA repair. However, iron requirements are not stable over time; blood loss, growth, pregnancy, changes in diet and even altitude all have powerful and sometimes acute effects on our need for iron and how we route it to tissues that need it – for example, in the case of blood loss, iron is released for erythropoiesis to help replace lost red blood cells. The second reason to regulate iron is in response to infection; evidence for a critical influence of iron on the outcome of infections is broad. Sequencing of microbial genomes reveals significant investment into iron acquisition, allowing pathogenic organisms to obtain iron from multiple host sources. Iron is required for pathogen proliferation and increased availability of host iron, either through experimental administration in animal models or, in humans, due to genetic causes or because of nutritive or therapeutic iron supplementation, exacerbates infection or increases its incidence. Part of the innate immune response to infection is to deny iron to the pathogen, slowing its growth and giving more time for other arms of immunity to mobilize. The hypoferremia of infection helps to inhibit growth of microbes in the bloodstream, and may be a critical response to prevent potentially fatal septicemia. Hepcidin is the liver-encoded peptide hormone that allows the body to maintain iron homeostasis, to rapidly release iron for erythropoiesis, and to lock iron away from microorganisms in response to infection. The ability to integrate these activities lies in the unique sensitivity of hepcidin expression to diverse physiological inputs. Transcription of hepcidin is enhanced by signals deriving from iron accumulation (through BMP/SMAD signaling) and from immune mediators (IL-6, IL-22, IFN-a), and is suppressed by expanded erythropoiesis via erythroferrone. In animal models the relative strengths of these signals determine hepcidin synthesis, and thus determine iron absorption, release, and storage. Our lab has been focusing on understanding hepcidin regulation in human populations where infectious disease, anemia, iron deficiency and inherited red cell disorders are all prevalent, for example sub-Saharan Africa and the Indian subcontinent. This lecture will describe how hepcidin analysis has helped us to understand the complex etiology of childhood anemia in malarious regions, suggested methods to improve iron therapeutic strategies, and indicated ways to use hepcidin diagnostically. The latter applications are now beginning to be tested clinically at the University of Oxford.