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Iron metabolism and innate immunity
A selection of talks on Metabolism & Nutrition
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- Prof. Emeritus Michael Gleeson
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I am Professor Tomas Ganz from the Department of Medicine at the University of California, Los Angeles. I will speak to you today about "Iron Metabolism and Innate Immunity".
Iron is an essential trace metal. It is a component of oxygen carriers as well as redox enzymes involved in energy metabolism, nucleotide synthesis, and other intermediary metabolism. Iron is also essential for microbes and it can be limiting for microbial growth.
During infection, microbes depend on host derived iron to supply themselves with this essential trace element. They use at least three different mechanisms to obtain the iron that they need. They secrete small organic molecules called siderophores, which are potent iron chelators. Once loaded with iron, the siderophores are taken back up by the microbes and the iron is utilized. Microbes also have pumps that are capable of transporting inorganic iron. And finally, some microbes are also capable of transporting host derived ferroproteins and reutilizing their iron for their own metabolic needs. Taking advantage of the extreme dependence of the invading
microorganisms on iron, the host responds by sequestering iron, making it more difficult for the microbes to obtain it. Intracellular microbes reside within the phagocytic vacuole. And this environment is subject to the activity of Nramp1, an iron transporter, which pumps iron from the phagocytic vacuole to the cytoplasm. This action is thought to decrease the concentration of iron in the phagocytic vacuole and makes it more difficult for the microbes to get this essential trace element. Humans and animals with mutated versions of Nramp1 are more susceptible to intracellular microbes. Extracellular microbes are subject to the activity of host defense cell derived lactoferrin and siderocalin, two proteins which bind iron. Lactoferrin binds ferric iron, and siderocalin binds iron within certain siderophores. Regardless of which of these two proteins acts, it deprives the extracellular microbes of an essential portion of their supply of iron. The iron regulatory hormone hepcidin, which is the main subject of today's lecture, acts on the transport mechanisms which supply iron to the extracellular fluid. Under the influence of hepcidin, iron becomes depleted in the extracellular fluid, making it again more difficult for the microbes to obtain it. This figure illustrates the effect of hepcidin in a mouse.