Content area
Full Text
REVIEWS
Iron homeostasis in host defence and inflammation
Tomas Ganz1,2 and Elizabeta Nemeth1
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.
In vertebrates, iron is required as a functional component of many proteins that are involved in a broad range of vital biochemical functions, such as oxygen transport and energy production (TABLE1). Iron is also essential for nearly all microorganisms, plants and invertebrate animals, in which it functions as a catalytic component of enzymes that mediate many redox reactions that are crucial for energy production and intermediary metabolism. Proteins may directly bind to iron or contain iron in the form of haem or ironsulfur clusters.
Although the modern study of iron homeostasis began more than 80 years ago, a detailed understanding of its molecular basis emerged only in the twentyfirst century and remains incomplete. Nevertheless, early investigators recognized a role for iron regulation in host defence. This led to the concept of irontargeted nutritional immunity as a set of constitutive and inducible mechanisms that deny iron to invading pathogens and thereby limit their ability to harm thehost1.
In healthy organisms, iron is maintained at a stable concentration in the plasma, and it is stored in hepatocytes and splenic and hepatic macrophages at constant levels, despite a fluctuating supply of iron from the diet. This homeostasis is controlled by an endocrine system that resembles those that regulate glucose and calcium concentrations. Central to systemic iron regulation is the liverderived hormone hepcidin (which is encoded by HAMP), which regulates, and is in turn regulated by, systemic iron levels. The transcription of HAMP is induced by increasing levels of iron in the plasma and in hepatic cellular stores. In turn, by causing degradation of...