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Ferrata Storti Foundation
Haematologica 2020 Volume 105(2):260-272
Iron metabolism and iron disorders revisited in the hepcidin era
Clara Camaschella,1 Antonella Nai1,2 and Laura Silvestri1,2
1Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan and 2Vita Salute San Raffaele University, Milan, Italy
ABSTRACT
Iron is biologically essential, but also potentially toxic; as such it is tightly controlled at cell and systemic levels to prevent both deficien- cy and overload. Iron regulatory proteins post-transcriptionally con- trol genes encoding proteins that modulate iron uptake, recycling and storage and are themselves regulated by iron. The master regulator of systemic iron homeostasis is the liver peptide hepcidin, which controls serum iron through degradation of ferroportin in iron-absorptive entero- cytes and iron-recycling macrophages. This review emphasizes the most recent findings in iron biology, deregulation of the hepcidin-ferroportin axis in iron disorders and how research results have an impact on clinical disorders. Insufficient hepcidin production is central to iron overload while hepcidin excess leads to iron restriction. Mutations of hemochro- matosis genes result in iron excess by downregulating the liver BMP- SMAD signaling pathway or by causing hepcidin-resistance. In iron- loading anemias, such as β-thalassemia, enhanced albeit ineffective ery- thropoiesis releases erythroferrone, which sequesters BMP receptor lig- ands, thereby inhibiting hepcidin. In iron-refractory, iron-deficiency ane- mia mutations of the hepcidin inhibitor TMPRSS6 upregulate the BMP- SMAD pathway. Interleukin-6 in acute and chronic inflammation increases hepcidin levels, causing iron-restricted erythropoiesis and ane- mia of inflammation in the presence of iron-replete macrophages. Our improved understanding of iron homeostasis and its regulation is having an impact on the established schedules of oral iron treatment and the choice of oral versus intravenous iron in the management of iron deficien- cy. Moreover it is leading to the development of targeted therapies for iron overload and inflammation, mainly centered on the manipulation of the hepcidin-ferroportin axis.
Introduction
Research advances in understanding the biological functions and homeostasis of iron have clarified its role in physiology and disease. Iron, essential for hemoglobin synthesis, is indispensable to all cells for the production of heme and iron-sulfur (Fe/S) clusters, which are components of proteins/enzymes involved in vital biolog- ical processes such as respiration, nucleic acid replication and repair, metabolic reactions and host defense. While essential for life, excess iron is toxic. The ability to accept/release electrons explains the propensity of iron to damage cell compo- nents and is the reason why body iron must be tightly regulated. The two-faced nature of iron is also evident in its disorders, which span from iron excess to iron deficiency and maldistribution, when some tissues are iron-loaded and others are iron-deficient.
In the new millennium studies of genetic and acquired iron disorders and the development of their corresponding murine models have identified novel iron genes, proteins and pathways and unveiled the central role of the hepcidin-ferro- portin axis in systemic iron homeostasis. This review summarizes recent advances in the understanding of iron trafficking, utilization and regulation, emphasizing the implications for iron disorders of hematologic interest; for further insights readers are directed to specific reviews.1-3
Correspondence:
CLARA CAMASCHELLA
camaschella.clara@hsr.it
Received: November 4, 2019. Accepted: December 18, 2019. Pre-published: January 16, 2020.
doi:10.3324/haematol.2019.232124
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/2/260
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