Iron is biologically essential, but also potentially toxic; as such it is tightly controlled at cell and systemic levels to prevent both deficiency and overload. Iron regulatory proteins post-transcriptionally control 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 enterocytes 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 ligands, 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 deficiency. 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.

/pdf/iron-metabolism-and-iron-disorders-revisited-in-the-hepcidin-3flyep0r8s.pdf

Iron metabolism and iron disorders revisited in the hepcidin era

Mechanisms controlling cellular and systemic iron homeostasis.

Immunometabolism explores how the intracellular metabolic pathways in immune cells can regulate their function under different micro-environmental and (patho-)-physiological conditions (Pearce, 2010; Buck et al., 2015; O'Neill and Pearce, 2016). In the last decade great advances have been made in studying and manipulating metabolic programs in immune cells. Immunometabolism has primarily focused on glycolysis, the TCA cycle and oxidative phosphorylation (OXPHOS) as well as free fatty acid synthesis and oxidation. These pathways are important for providing the energy needs of cell growth, membrane rigidity, cytokine production and proliferation. In this review, we will however, highlight the specific role of iron metabolism at the cellular and organismal level, as well as how the bioavailability of this metal orchestrates complex metabolic programs in immune cell homeostasis and inflammation. We will also discuss how dysregulation of iron metabolism contributes to alterations in the immune system and how these novel insights into iron regulation can be targeted to metabolically manipulate immune cell function under pathophysiological conditions, providing new therapeutic opportunities for autoimmunity and cancer.

The Role of Iron Regulation in Immunometabolism and Immune-Related Disease

Hepcidin, the iron-regulatory hormone, determines plasma iron concentrations and total body iron content. Hepcidin, secreted by hepatocytes, functions by controlling the activity of the cellular iron exporter ferroportin, which delivers iron to plasma from intestinal iron absorption and from iron stores. Hepcidin concentration in plasma is increased by iron loading and inflammation and is suppressed by erythropoietic stimulation and during pregnancy. Hepcidin deficiency causes iron overload in hemochromatosis and anemias with ineffective erythropoiesis. Hepcidin excess causes iron-restrictive anemias including anemia of inflammation. The development of hepcidin diagnostics and therapeutic agonists and antagonists should improve the treatment of iron disorders.

https://www.annualreviews.org/doi/pdf/10.1146/annurev-med-043021-032816

Hepcidin and Iron in Health and Disease

Basics and principles of cellular and systemic iron homeostasis

The liver iron hormone hepcidin regulates body iron homeostasis by blocking iron export via ferroportin. Hepcidin transcription is controlled by the BMP-SMAD pathway, whose activation requires BMP2, BMP6, type I (ALK2 and ALK3) and type II (ACVR2A and BMPR2) BMP receptors. BMP2 and BMP6 are mainly expressed by liver sinusoidal endothelial cells and their deletion in mice causes iron overload due to decreased hepcidin mRNA expression. BMP type II receptors show a redundant function in hepcidin regulation in vivo, while ALK2 and ALK3 have a non-redundant role. The current model suggests that ALK2 is mainly involved in BMP6-dependent hepcidin upregulation in conditions of iron overload and is inhibited by FKBP12, whereas ALK3 maintains basal hepcidin expression and signals preferentially in response to BMP2. Hereditary hemochromatosis (HH), characterized by iron overload due to inappropriately low hepcidin production, is caused by mutations in

pdf/hemochromatosis-proteins-are-dispensable-for-the-acute-30d5gazuxd.pdf

Hemochromatosis proteins are dispensable for the acute hepcidin response to BMP2

The expression of the iron regulatory hormone hepcidin in hepatocytes is regulated by the BMP‐SMAD pathway through the type I receptors ALK2 and ALK3, the type II receptors ACVR2A and BMPR2, and the ligands BMP2 and BMP6. We previously identified the immunophilin FKBP12 as a new hepcidin inhibitor that acts by blocking ALK2. Both the physiologic ALK2 ligand BMP6 and the immunosuppressive drug Tacrolimus (TAC) displace FKBP12 from ALK2 and activate the signaling. However, the molecular mechanism whereby FKBP12 regulates BMP‐SMAD pathway activity and thus hepcidin expression remains unclear. Here, we show that FKBP12 acts by modulating BMP receptor interactions and ligand responsiveness. We first demonstrate that in primary murine hepatocytes TAC regulates hepcidin expression exclusively via FKBP12. Downregulation of the BMP receptors reveals that ALK2, to a lesser extent ALK3, and ACVR2A are required for hepcidin upregulation in response to both BMP6 and TAC. Mechanistically, TAC and BMP6 increase ALK2 homo‐oligomerization and ALK2–ALK3 hetero‐oligomerization and the interaction between ALK2 and the type II receptors. By acting on the same receptors, TAC and BMP6 cooperate in BMP pathway activation and hepcidin expression both in vitro and in vivo. Interestingly, the activation state of ALK3 modulates its interaction with FKBP12, which may explain the cell‐specific activity of FKBP12. Overall, our results identify the mechanism whereby FKBP12 regulates the BMP‐SMAD pathway and hepcidin expression in hepatocytes, and suggest that FKBP12–ALK2 interaction is a potential pharmacologic target in disorders caused by defective BMP‐SMAD signaling and characterized by low hepcidin and high BMP6 expression.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ajh.26961

FKBP12 inhibits hepcidin expression by modulating BMP receptors interaction and ligand responsiveness in hepatocytes

Hepcidin, the main regulator of iron metabolism, is synthesized and released by hepatocytes in response to increased body iron concentration and inflammation. Deregulation of hepcidin expression is a common feature of genetic and acquired iron disorders: in Hereditary Hemochromatosis (HH) and iron-loading anemias low hepcidin causes iron overload, while in Iron Refractory Iron Deficiency Anemia (IRIDA) and anemia of inflammation (AI), high hepcidin levels induce iron-restricted erythropoiesis. Hepcidin expression in the liver is mainly controlled by the BMP-SMAD pathway, activated in a paracrine manner by BMP2 and BMP6 produced by liver sinusoidal endothelial cells. The BMP type I receptors ALK2 and ALK3 are responsible for iron-dependent hepcidin upregulation and basal hepcidin expression, respectively. Characterization of animal models with genetic inactivation of the key components of the pathway has suggested the existence of two BMP/SMAD pathway branches: the first ALK3 and HH proteins dependent, responsive to BMP2 for basal hepcidin activation, and the second ALK2 dependent, activated by BMP6 in response to increased tissue iron. The erythroid inhibitor of hepcidin Erythroferrone also impacts on the liver BMP-SMAD pathway although its effect is blunted by pathway hyper-activation. The liver BMP-SMAD pathway is required also in inflammation to cooperate with JAK2/STAT3 signaling for full hepcidin activation. Pharmacologic targeting of BMP-SMAD pathway components or regulators may improve the outcome of both genetic and acquired disorders of iron overload and deficiency by increasing or inhibiting hepcidin expression.

Hepcidin and the BMP-SMAD pathway: An unexpected liaison.

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Hemochromatosis proteins are dispensable for the acute hepcidin response to BMP2

FKBP12 inhibits hepcidin expression by modulating BMP receptors interaction and ligand responsiveness in hepatocytes

Hepcidin and the BMP-SMAD pathway: An unexpected liaison.