Hepcidin as the central mediator of anemia of inflammation

Anemia of inflammation (AI, anemia of chronic disease) occurs during a wide variety of inflammatory disorders including infections, autoimmune diseases, renal failure, and malignancy. It is associated with significant morbidity, may increase mortality rates in some diseases, and increases healthcare costs dramatically. The principal finding that differentiates AI from other chronic anemias is hypoferremia in the setting of preserved iron stores. Until recently, little was known about the normal molecular regulation of iron transport or its dysregulation in AI. The discovery of the negative iron-regulatory hormone hepcidin and the cellular iron exporter ferroportin in the past 7 years strongly suggested that hepcidin may be the mediator of AI. This work shows that the effect of increased hepcidin levels recapitulates the findings of AI. We show that mice given exogenous hepcidin rapidly develop hypoferremia in a dose-dependent fashion. Hepcidin traffics to organs rich in ferroportin supporting the in vitro finding that hepcidin induces the degradation of ferroportin. Furthermore, mice with tumors overexpressing hepcidin develop more severe hypoferremia and anemia than mice with control tumors. This work also demonstrates that hepcidin is directly regulated by inflammatory mediators. We found that IL-6 is an important regulator of hepcidin, especially during acute inflammation, but that other mediators may play a role during prolonged inflammation. Finally we demonstrate that there is a feedback mechanism to limit the severity of anemia that occurs in response to increased hepcidin. Hepcidin is decreased during phlebotomy-induced anemia but inhibitors of erythropoiesis reverse the effect of anemia. These results indicate that the suppression of hepcidin during anemia is predominantly through increased erythropoiesis or the fall in serum or tissue iron secondary to increased iron utilization. In the aggregate, the studies presented in this thesis show that hepcidin is the principal mediator of the anemia of inflammation.