Novel Insights Into Systemic Iron Regulation
Authors: Silvestri Laura , Pagani Alessia , Nai Antonella , Camaschella Clara 
Published: October 2019

Abstract
Iron, an essential element in mammals, is absorbed by duodenal enterocytes, enters the circulation through the iron exporter ferroportin, (FPN), circulates bound to transferrin and is uptaken through Transferrin Receptor 1. If in excess, iron is stored in macrophages and hepatocytes and released when needed. To maintain systemic iron homeostasis and to avoid the formation of "non transferrin bound iron" (NTBI), a highly reactive form which causes organ damage, the liver synthetizes hepcidin that, binding FPN, blocks iron export to the circulation. Hepcidin integrates signals from body iron, erythropoiesis and inflammatory cytokines. Defective hepcidin production causes iron overload and organ failure in Hereditary Hemochromatosis and Thalassemia; hepcidin excess leads to anemia in Iron Refractory iron Deficiency Anemia (IRIDA) and Anemia of Inflammation (AI).
In hepatocytes hepcidin is under the control of the BMP-SMAD pathway, which is activated in a paracrine manner by BMP2 and BMP6 produced by liver sinusoidal endothelial cells. BMP2 maintains hepcidin basal levels, while BMP6 controls its expression in response to iron. The two ligands have different affinity for BMP type I receptors ALK2 and ALK3, suggesting two distinct branches of the hepcidin activation pathway. This possibility is consistent with the non-redundant function of BMP2 and BMP6, the different iron phenotype of hepatocyte-conditional ALK2 and ALK3 KO mice and the residual ability of BMP6 to activate hepcidin in hemochromatosis mice. Moreover ALK2, but not ALK3, is inhibited by the immunophilin FKBP12 in the absence of ligands. The BMP pathway activation depends upon the coreceptor hemojuvelin (HJV), the MHC class I protein HFE and the second transferrin receptor (TFR2). Mutations of all these proteins lead to decreased hepcidin expression in hemochromatosis.
Hepcidin expression is inhibited in iron deficiency, hypoxia and when erythropoiesis is increased. Inhibitors are the liver transmembrane serine protease TMPRSS6, whose genetic inactivation causes IRIDA, and the erythroid hormone erythroferrone (ERFE), which is released by erythropoietin-stimulated erythroblasts. The mechanism of hepcidin inhibition by ERFE is unclear; still to allow ERFE function the BMP-SMAD pathway has not to be hyperactive. Intriguingly, both iron deficiency and erythropoiesis require epigenetic modifications at the hepcidin locus with HDAC3-dependent reversible loss of H3K9ac and H3K4me3.
Hepcidin also acts as an antimicrobial peptide since its expression, increased by proinflammatory cytokines, such as IL6 through JAK2-STAT3 signaling, restricts iron availability for microbial growth. This first-line of defense against infections negatively influences erythropoiesis since chronic hepcidin activation causes AI. Despite persistent JAK2-STAT3 activation, inhibition of the BMP-SMAD pathway reduces hepcidin activation in AI experimental rodent models, suggesting that hepcidin activation in inflammation requires a functional BMP-SMAD pathway. Independently from hepcidin, inflammation also reduces FPN mRNA levels, favoring macrophage iron sequestration.
The identification of hepcidin-ferroportin axis molecular players has translational implications. In primary and secondary iron overload hepcidin agonists (hepcidin peptides or mimics, agents that inhibit the hepcidin inhibitor TMPRSS6 and likely the ALK2-inhibitor FKBP12) and ferroportin inhibitors are potentially useful to prevent iron overload and/or to favor iron redistribution to macrophages. In case of AI, hepcidin antagonists (including anti-hepcidin, anti-HJV and anti-BMP6 monoclonal antibodies, L-enantiomeric oligonucleotides targeting hepcidin, siRNA against hepcidin, non-anticoagulant heparins, the ALK2 inhibitor momelotinib) might improve erythropoiesis increasing iron availability.
The effect of some agents that have now entered the clinical phase will become apparent in the coming years.

Disclosures
Camaschella: vifor Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.