Key Points
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Iron metabolism is a tightly regulated physiological process that has relatively low redundancy, and its deregulation often leads to iron deficiency or iron overload.
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Iron deficiency and iron overload are historically associated with erythroid disorders; however, deregulated iron metabolism is also implicated in numerous ageing-related, non-haematological disorders, including neurodegenerative disorders, atherosclerosis and cancer.
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Intracellular iron is directly involved in the formation of reactive oxygen species, which can cause cellular oxidative damage. Reactive oxygen species are also important for ferroptosis, a form of non-apoptotic cell death.
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The internalization of iron by macrophages can modulate macrophage activity towards a pro-inflammatory phenotype, which may also depend on the pathway of iron intake.
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Agents that interfere with key regulators of iron metabolism and cellular iron trafficking represent a promising new class of therapeutic agents for various diseases because these agents exploit pathological pathways that are complementary to those targeted by existing treatments.
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Targeting therapeutics to diseased tissues that express high levels of transferrin receptor is a strategy that is used by several agents currently in clinical development, and extending this strategy towards other iron metabolism-associated cellular transporters may be advantageous.
Abstract
Iron fulfils a central role in many essential biochemical processes in human physiology; thus, proper processing of iron is crucial. Although iron metabolism is subject to relatively strict physiological control, numerous disorders, such as cancer and neurodegenerative diseases, have recently been linked to deregulated iron homeostasis. Consequently, iron metabolism constitutes a promising and largely unexploited therapeutic target for the development of new pharmacological treatments for these diseases. Several iron metabolism-targeted therapies are already under clinical evaluation for haematological disorders, and these and newly developed therapeutic agents are likely to have substantial benefit in the clinical management of iron metabolism-associated diseases, for which few efficacious treatments are currently available.
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References
Rouault, T. A. Iron-sulfur proteins hiding in plain sight. Nat. Chem. Biol. 11, 442–445 (2015).
Hohenberger, J., Ray, K. & Meyer, K. The biology and chemistry of high-valent iron–oxo and iron–nitrido complexes. Nat. Commun. 3, 720 (2012).
Ganz, T. Systemic iron homeostasis. Physiol. Rev. 93, 1721–1741 (2013).
Camaschella, C. Iron-deficiency anemia. N. Engl. J. Med. 372, 1832–1843 (2015).
Rivella, S. β-Thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies. Haematologica 100, 418–430 (2015).
Stadtman, E. R. Protein oxidation and aging. Science 257, 1220–1224 (1992).
Fenton, H. J. H. Oxidation of tartaric acid in presence of iron. J. Chem. Soc. Trans. 65, 899–910 (1894).
Haber, F. & Weiss, J. Über die Katalyse des Hydroperoxydes. Naturwissenschaften 20, 948–950 (in German) (1932).
Park, C. H., Valore, E. V., Waring, A. J. & Ganz, T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J. Biol. Chem. 276, 7806–7810 (2001).
Krause, A. et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 480, 147–150 (2000). References 9 and 10 describe for the first time the isolation and characterization of hepcidin, which was then shown to have moderate antimicrobial activity.
Nicolas, G. et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc. Natl Acad. Sci. USA 98, 8780–8785 (2001). The first study to demonstrate the role of hepcidin as the master regulator of iron metabolism.
Donovan, A. et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403, 776–781 (2000).
Nemeth, E. et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306, 2090–2093 (2004). This study demonstrates that hepcidin regulates systemic iron homeostasis by binding ferroportin and inducing its internalization, thereby blocking the cellular egress of iron.
McKie, A. T. et al. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol. Cell 5, 299–309 (2000).
Donovan, A. et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab. 1, 191–200 (2005).
Abboud, S. & Haile, D. J. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J. Biol. Chem. 275, 19906–19912 (2000). References 12, 14 and 16 provide the first reports of the isolation and characterization of ferroportin, demonstrating its role in cellular iron export.
Aisen, P., Leibman, A. & Zweier, J. Stoichiometric and site characteristics of the binding of iron to human transferrin. J. Biol. Chem. 253, 1930–1937 (1978).
Fotticchia, I. et al. Energetics of ligand–receptor binding affinity on endothelial cells: an in vitro model. Colloids Surf. B Biointerfaces 144, 250–256 (2016).
Dautry-Varsat, A., Ciechanover, A. & Lodish, H. F. pH and the recycling of transferrin during receptor-mediated endocytosis. Proc. Natl Acad. Sci. USA 80, 2258–2262 (1983).
Trinder, D., Zak, O. & Aisen, P. Transferrin receptor-independent uptake of differic transferrin by human hepatoma cells with antisense inhibition of receptor expression. Hepatology 23, 1512–1520 (1996).
Gunshin, H. et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388, 482–488 (1997). This study identifies DMT1, which was then shown to be involved in the transport of bivalent cations, in particular Fe(II).
Liuzzi, J. P., Aydemir, F., Nam, H., Knutson, M. D. & Cousins, R. J. Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells. Proc. Natl Acad. Sci. USA 103, 13612–13617 (2006).
Wang, C.-Y. et al. ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading. J. Biol. Chem. 287, 34032–34043 (2012).
Fleming, M. D. et al. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat. Genet. 16, 383–386 (1997).
Fleming, M. D. et al. Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc. Natl Acad. Sci. USA 95, 1148–1153 (1998).
Shawki, A. et al. Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese. Am. J. Physiol. Gastrointest. Liver Physiol. 309, G635–G647 (2015).
Mims, M. P. et al. Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload. Blood 105, 1337–1342 (2005).
Canonne-Hergaux, F., Zhang, A.-S., Ponka, P. & Gros, P. Characterization of the iron transporter DMT1 (NRAMP2/DCT1) in red blood cells of normal and anemic mk/mk mice. Blood 98, 3823–3830 (2001).
Jenkitkasemwong, S. et al. SLC39A14 is required for the development of hepatocellular iron overload in murine models of hereditary hemochromatosis. Cell Metab. 22, 138–150 (2015). This study identifies ZIP14 as a key cellular Fe(II) importer that is specifically involved in iron uptake in tissues typically affected by iron overload.
McKie, A. T. et al. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 291, 1755–1759 (2001).
Ohgami, R. S. et al. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat. Genet. 37, 1264–1269 (2005).
Ohgami, R. S., Campagna, D. R., McDonald, A. & Fleming, M. D. The Steap proteins are metalloreductases. Blood 108, 1388–1394 (2006).
Tripathi, A. K. et al. Prion protein functions as a ferrireductase partner for ZIP14 and DMT1. Free Radic. Biol. Med. 84, 322–330 (2015).
Singh, A. et al. Prion protein regulates iron transport by functioning as a ferrireductase. J. Alzheimers Dis. 35, 541–552 (2013).
Kristiansen, M. et al. Identification of the haemoglobin scavenger receptor. Nature 409, 198–201 (2001).
Andersen, C. B. F. et al. Structure of the haptoglobin–haemoglobin complex. Nature 489, 456–459 (2012). References 35 and 36 describe the identification of the macrophage-associated haemoglobin receptor CD163 and the structural characterization of the haptoglobin–haemoglobin complex that is bound and internalized by CD163.
Hvidberg, V. et al. Identification of the receptor scavenging hemopexin–heme complexes. Blood 106, 2572–2579 (2005).
Rajagopal, A. et al. Haem homeostasis is regulated by the conserved and concerted functions of HRG-1 proteins. Nature 453, 1127–1131 (2008).
Duffy, S. P. et al. The Fowler syndrome-associated protein FLVCR2 is an importer of heme. Mol. Cell. Biol. 30, 5318–5324 (2010).
White, C. et al. HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis. Cell Metab. 17, 261–270 (2013).
Li, J. Y. et al. Scara5 is a ferritin receptor mediating non-transferrin iron delivery. Dev. Cell 16, 35–46 (2009).
Li, L. et al. Binding and uptake of H-ferritin are mediated by human transferrin receptor-1. Proc. Natl Acad. Sci. USA 107, 3505–3510 (2010).
Moss, D., Powell, L. W., Arosio, P. & Halliday, J. W. Characterization of the ferritin receptors of human T lymphoid (MOLT-4) cells. J. Lab. Clin. Med. 119, 273–279 (1992).
Chen, T. T. et al. TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis. J. Exp. Med. 202, 955–965 (2005).
Shaw, G. C. et al. Mitoferrin is essential for erythroid iron assimilation. Nature 440, 96–100 (2006).
Bou-Abdallah, F. The iron redox and hydrolysis chemistry of the ferritins. Biochim. Biophys. Acta 1800, 719–731 (2010).
Leibold, E. A. & Munro, H. N. Cytoplasmic protein binds in vitro to a highly conserved sequence in the 5′ untranslated region of ferritin heavy- and light-subunit mRNAs. Proc. Natl Acad. Sci. USA 85, 2171–2175 (1988).
Rouault, T. A., Hentze, M. W., Caughman, S. W., Harford, J. B. & Klausner, R. D. Binding of a cytosolic protein to the iron-responsive element of human ferritin messenger RNA. Science 241, 1207–1210 (1988).
Vashchenko, G. & MacGillivray, R. T. A. Multi-copper oxidases and human iron metabolism. Nutrients 5, 2289–2313 (2013).
Ghosh, S., Hevi, S. & Chuck, S. L. Regulated secretion of glycosylated human ferritin from hepatocytes. Blood 103, 2369–2376 (2004).
Cohen, L. A. et al. Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood 116, 1574–1584 (2010).
Mancias, J. D., Wang, X., Gygi, S. P., Harper, J. W. & Kimmelman, A. C. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature 509, 105–109 (2014).
Keel, S. B. et al. A heme export protein is required for red blood cell differentiation and iron homeostasis. Science 319, 825–828 (2008).
Taher, A. T. et al. Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study. Blood 115, 1886–1892 (2010).
Finberg, K. E. et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat. Genet. 40, 569–571 (2008).
Gardenghi, S. et al. Distinct roles for hepcidin and interleukin-6 in the recovery from anemia in mice injected with heat-killed Brucella abortus. Blood 123, 1137–1145 (2014).
Canali, S. et al. Activin B induces noncanonical SMAD1/5/8 signaling via BMP type I receptors in hepatocytes: evidence for a role in hepcidin induction by inflammation in male mice. Endocrinology 157, 1146–1162 (2016).
Weiss, G. & Schett, G. Anaemia in inflammatory rheumatic diseases. Nat. Rev. Rheumatol. 9, 205–215 (2013).
Eaton, J. W. & Qian, M. Molecular bases of cellular iron toxicity. Free Radic. Biol. Med. 32, 833–840 (2002).
Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012). This study is the first to describe ferroptosis, demonstrating the dependence of this distinct form of cell death on the availability of intracellular iron.
Skouta, R. et al. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J. Am. Chem. Soc. 136, 4551–4556 (2014).
Kang, Y., Tiziani, S., Park, G., Kaul, M. & Paternostro, G. Cellular protection using Flt3 and PI3Kα inhibitors demonstrates multiple mechanisms of oxidative glutamate toxicity. Nat. Commun. 5, 3672 (2014).
Friedmann Angeli, J. P. et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol. 16, 1180–1191 (2014).
Linkermann, A. et al. Synchronized renal tubular cell death involves ferroptosis. Proc. Natl Acad. Sci. USA 111, 16836–16841 (2014).
Jiang, L. et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520, 57–62 (2015).
Sun, X. et al. HSPB1 as a novel regulator of ferroptotic cancer cell death. Oncogene 34, 5617–5625 (2015).
Yang, W. S. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317–331 (2014).
Dixon, S. J. & Stockwell, B. R. The role of iron and reactive oxygen species in cell death. Nat. Chem. Biol. 10, 9–17 (2014).
Sabharwal, S. S. & Schumacker, P. T. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel? Nat. Rev. Cancer 14, 709–721 (2014).
Conrad, M., Angeli, J. P. F., Vandenabeele, P. & Stockwell, B. R. Regulated necrosis: disease relevance and therapeutic opportunities. Nat. Rev. Drug Discov. 15, 348–366 (2016).
Chow, A. et al. CD169+ macrophages provide a niche promoting erythropoiesis under homeostasis and stress. Nat. Med. 19, 429–436 (2013).
Ramos, P. et al. Macrophages support pathological erythropoiesis in polycythemia vera and β-thalassemia. Nat. Med. 19, 437–445 (2013).
She, H. et al. Iron activates NF-κB in Kupffer cells. Am. J. Physiol. Gastrointest. Liver Physiol. 283, G719–G726 (2002).
Zhang, Z. et al. Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses. Blood 118, 1912–1922 (2011).
Zanganeh, S. et al. Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nat. Nanotechnol. 11, 986–994 (2016). This study demonstrates the capacity of iron to modulate the activity of intratumoural macrophages to an antitumoural phenotype, which could be exploited as an anticancer strategy.
Sindrilaru, A. et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J. Clin. Invest. 121, 985–997 (2011). This study is the first to directly link the inflammatory phenotype of macrophages to their iron load.
Vinchi, F. et al. Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease. Blood 127, 473–486 (2016).
Jabara, H. H. et al. A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Nat. Genet. 48, 74–78 (2016).
Wandersman, C. & Delepelaire, P. Bacterial iron sources: from siderophores to hemophores. Annu. Rev. Microbiol. 58, 611–647 (2004).
Bao, G. et al. Iron traffics in circulation bound to a siderocalin (Ngal)–catechol complex. Nat. Chem. Biol. 6, 602–609 (2010).
Flo, T. H. et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432, 917–921 (2004).
Arezes, J. et al. Hepcidin-induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium Vibrio vulnificus. Cell Host Microbe 17, 47–57 (2015).
Chen, S. et al. Transforming growth factor β1 (TGF-β1) activates hepcidin mRNA expression in hepatocytes. J. Biol. Chem. 291, 13160–13174 (2016).
Guida, C. et al. A novel inflammatory pathway mediating rapid hepcidin-independent hypoferremia. Blood 125, 2265–2275 (2015).
Piskounova, E. et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527, 186–191 (2015).
Torti, S. V. & Torti, F. M. Iron and cancer: more ore to be mined. Nat. Rev. Cancer 13, 342–355 (2013).
Bystrom, L. M. & Rivella, S. Cancer cells with irons in the fire. Free Radic. Biol. Med. 79, 337–342 (2015).
Kim, K.-S., Son, H.-G., Hong, N.-S. & Lee, D.-H. Associations of serum ferritin and transferrin saturation with all-cause, cancer, and cardiovascular disease mortality: Third National Health and Nutrition Examination Survey follow-up study. J. Prev. Med. Public Health 45, 196–203 (2012).
Ashmore, J. H., Rogers, C. J., Kelleher, S. L., Lesko, S. M. & Hartman, T. J. Dietary iron and colorectal cancer risk: a review of human population studies. Crit. Rev. Food Sci. Nutr. 56, 1012–1020 (2016).
Miller, L. D. et al. An iron regulatory gene signature predicts outcome in breast cancer. Cancer Res. 71, 6728–6737 (2011).
Pinnix, Z. K. et al. Ferroportin and iron regulation in breast cancer progression and prognosis. Sci. Transl Med. 2, 43ra56 (2010). This study demonstrates an inverse relationship between ferroportin expression and breast cancer progression in vitro, in vivo and in four-patient cohorts.
Habashy, H. O. et al. Transferrin receptor (CD71) is a marker of poor prognosis in breast cancer and can predict response to tamoxifen. Breast Cancer Res. Treat. 119, 283–293 (2009).
Jeong, S. M., Hwang, S. & Seong, R. H. Transferrin receptor regulates pancreatic cancer growth by modulating mitochondrial respiration and ROS generation. Biochem. Biophys. Res. Commun. 471, 373–379 (2016).
Schonberg, D. L. et al. Preferential iron trafficking characterizes glioblastoma stem-like cells. Cancer Cell 28, 441–455 (2015).
Högemann-Savellano, D. et al. The transferrin receptor: a potential molecular imaging marker for human cancer. Neoplasia 5, 495–506 (2003).
Isobe, T. et al. Human STEAP3 maintains tumor growth under hypoferric condition. Exp. Cell Res. 317, 2582–2591 (2011).
Savci-Heijink, C. D., Halfwerk, H., Koster, J. & Vijver, M. J. A novel gene expression signature for bone metastasis in breast carcinomas. Breast Cancer Res. Treat. 156, 249–259 (2016).
Tesfay, L. et al. Hepcidin regulation in prostate and its disruption in prostate cancer. Cancer Res. 75, 2254–2263 (2015).
Chen, Y. et al. Disordered signaling governing ferroportin transcription favors breast cancer growth. Cell. Signal. 27, 168–176 (2015).
Zhang, S. et al. Disordered hepcidin–ferroportin signaling promotes breast cancer growth. Cell. Signal. 26, 2539–2550 (2014).
Marques, O. et al. Local iron homeostasis in the breast ductal carcinoma microenvironment. BMC Cancer 16, 187 (2016).
Sanders, A. J. et al. Genetic upregulation of matriptase-2 reduces the aggressiveness of prostate cancer cells in vitro and in vivo and affects FAK and paxillin localisation. J. Cell. Physiol. 216, 780–789 (2008).
Chen, Y. et al. Myeloid zinc-finger 1 (MZF-1) suppresses prostate tumor growth through enforcing ferroportin-conducted iron egress. Oncogene 34, 3839–3847 (2015).
Calzolari, A. et al. Transferrin receptor 2 is frequently and highly expressed in glioblastomas. Transl Oncol. 3, 123–134 (2010).
Ward, R. J., Zucca, F. A., Duyn, J. H., Crichton, R. R. & Zecca, L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 13, 1045–1060 (2014).
Simpson, I. A. et al. A novel model for brain iron uptake: introducing the concept of regulation. J. Cereb. Blood Flow Metab. 35, 48–57 (2015).
McCarthy, R. C. & Kosman, D. J. Mechanisms and regulation of iron trafficking across the capillary endothelial cells of the blood–brain barrier. Front. Mol. Neurosci. 8, 31 (2015).
Nielsen, J. E., Jensen, L. N. & Krabbe, K. Hereditary haemochromatosis: a case of iron accumulation in the basal ganglia associated with a parkinsonian syndrome. J. Neurol. Neurosurg. Psychiatry 59, 318–321 (1995).
Dekker, M. C. J. et al. Mutations in the hemochromatosis gene (HFE), Parkinson's disease and parkinsonism. Neurosci. Lett. 348, 117–119 (2003).
Wang, X.-S. et al. Increased incidence of the Hfe mutation in amyotrophic lateral sclerosis and related cellular consequences. J. Neurol. Sci. 227, 27–33 (2004).
Bucossi, S. et al. Association of K832R and R952K SNPs of Wilson's disease gene with Alzheimer's disease. J. Alzheimers Dis. 29, 913–919 (2012).
Kong, S. M. Y. et al. Parkinson's disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes α-synuclein externalization via exosomes. Hum. Mol. Genet. 23, 2816–2833 (2014).
Kell, D. B. Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson's, Huntington's, Alzheimer's, prions, bactericides, chemical toxicology and others as examples. Arch. Toxicol. 84, 825–889 (2010).
Rouault, T. A. Iron metabolism in the CNS: implications for neurodegenerative diseases. Nat. Rev. Neurosci. 14, 551–564 (2013).
Singh, N., Das, D., Singh, A. & Mohan, M. L. Prion protein and metal interaction: physiological and pathological implications. Curr. Issues Mol. Biol. 12, 99–107 (2010).
Singh, A. et al. Abnormal brain iron homeostasis in human and animal prion disorders. PLoS Pathog. 5, e1000336 (2009).
Dringen, R., Bishop, G. M., Koeppe, M., Dang, T. N. & Robinson, S. R. The pivotal role of astrocytes in the metabolism of iron in the brain. Neurochem. Res. 32, 1884–1890 (2007).
Urrutia, P. et al. Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells. J. Neurochem. 126, 541–549 (2013).
Raha-Chowdhury, R. et al. Expression and cellular localization of hepcidin mRNA and protein in normal rat brain. BMC Neurosci. 16, 24 (2015).
Raha, A. A., Vaishnav, R. A., Friedland, R. P., Bomford, A. & Raha-Chowdhury, R. The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer's disease. Acta Neuropathol. Commun. 1, 55 (2013).
Wang, J., Jiang, H. & Xie, J.-X. Ferroportin1 and hephaestin are involved in the nigral iron accumulation of 6-OHDA-lesioned rats. Eur. J. Neurosci. 25, 2766–2772 (2007).
Halon, M. et al. Changes in skeletal muscle iron metabolism outpace amyotrophic lateral sclerosis onset in transgenic rats bearing the G93A hmSOD1 gene mutation. Free Radic. Res. 48, 1363–1370 (2014).
Zarruk, J. G. et al. Expression of iron homeostasis proteins in the spinal cord in experimental autoimmune encephalomyelitis and their implications for iron accumulation. Neurobiol. Dis. 81, 93–107 (2015).
Kroner, A. et al. TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. Neuron 83, 1098–1116 (2014).
Mehta, V. et al. Iron is a sensitive biomarker for inflammation in multiple sclerosis lesions. PLoS ONE 8, e57573 (2013).
Jeong, S. Y. & David, S. Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J. Biol. Chem. 278, 27144–27148 (2003).
Ayton, S., Faux, N. G. & Bush, A. I. & Alzheimer's Disease Neuroimaging Initiative. Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE. Nat. Commun. 6, 6760 (2015).
Baraibar, M. A., Barbeito, A. G., Muhoberac, B. B. & Vidal, R. A mutant light-chain ferritin that causes neurodegeneration has enhanced propensity toward oxidative damage. Free Radic. Biol. Med. 52, 1692–1697 (2012).
Biasiotto, G., Lorenzo, D. D., Archetti, S. & Zanella, I. Iron and neurodegeneration: is ferritinophagy the link? Mol. Neurobiol. 53, 5542–5574 (2016).
Stadler, N., Lindner, R. A. & Davies, M. J. Direct detection and quantification of transition metal ions in human atherosclerotic plaques: evidence for the presence of elevated levels of iron and copper. Arterioscler. Thromb. Vasc. Biol. 24, 949–954 (2004).
Satchell, L. & Leake, D. S. Oxidation of low-density lipoprotein by iron at lysosomal pH: implications for atherosclerosis. Biochemistry 51, 3767–3775 (2012).
Sullivan, J. L. Do hemochromatosis mutations protect against iron-mediated atherogenesis? Circ. Cardiovasc. Genet. 2, 652–657 (2009).
Robbins, C. S. et al. Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat. Med. 19, 1166–1172 (2013).
Chinetti-Gbaguidi, G., Colin, S. & Staels, B. Macrophage subsets in atherosclerosis. Nat. Rev. Cardiol. 12, 10–17 (2015).
Gursel, O. et al. Premature atherosclerosis in children with β-thalassemia major. J. Pediatr. Hematol. Oncol. 34, 630–634 (2012).
Cheung, Y. F., Chow, P. C., Chan, G. C. & Ha, S. Y. Carotid intima-media thickness is increased and related to arterial stiffening in patients with beta-thalassaemia major. Br. J. Haematol. 135, 732–734 (2006).
Li, J. J. et al. Hepcidin destabilizes atherosclerotic plaque via overactivating macrophages after erythrophagocytosis. Arterioscler. Thromb. Vasc. Biol. 32, 1158–1166 (2012).
Kautz, L. et al. Testing the iron hypothesis in a mouse model of atherosclerosis. Cell Rep. 5, 1436–1442 (2013).
Mehta, N. U. et al. Apolipoprotein E−/− mice lacking hemopexin develop increased atherosclerosis via mechanisms that include oxidative stress and altered macrophage function. Arterioscler. Thromb. Vasc. Biol. 36, 1152–1163 (2016).
Boyle, J. J. et al. Activating transcription factor 1 directs mhem atheroprotective macrophages through coordinated iron handling and foam cell protection. Circ. Res. 110, 20–33 (2012).
Bories, G. et al. Liver X receptor activation stimulates iron export in human alternative macrophages. Circ. Res. 113, 1196–1205 (2013).
Fernández-Real, J. M., McClain, D. & Manco, M. Mechanisms linking glucose homeostasis and iron metabolism toward the onset and progression of type 2 diabetes. Diabetes Care 38, 2169–2176 (2015).
Kim, B.-J. et al. Iron overload accelerates bone loss in healthy postmenopausal women and middle-aged men: a 3-year retrospective longitudinal study. J. Bone Miner. Res. 27, 2279–2290 (2012).
Camacho, A. et al. Iron overload in a murine model of hereditary hemochromatosis is associated with accelerated progression of osteoarthritis under mechanical stress. Osteoarthritis Cartilage 24, 494–502 (2016).
Dunaief, J. L. et al. Macular degeneration in a patient with aceruloplasminemia, a disease associated with retinal iron overload. Ophthalmology 112, 1062–1065 (2005).
Fargion, S., Valenti, L. & Fracanzani, A. L. Beyond hereditary hemochromatosis: new insights into the relationship between iron overload and chronic liver diseases. Dig. Liver Dis. 43, 89–95 (2011).
Keberle, H. The biochemistry of desferrioxamine and its relation to iron metabolism. Ann. NY Acad. Sci. 119, 758–768 (1964). This study describes the isolation and characterization of desferrioxamine B from Streptomyces pilosus , which would become the first iron chelator to be used in the clinic.
Borgna-Pignatti, C. et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica 89, 1187–1193 (2004).
Olivieri, N. F. et al. Iron-chelation therapy with oral deferiprone in patients with thalassemia major. N. Engl. J. Med. 332, 918–922 (1995).
Nick, H. et al. Development of tridentate iron chelators: from desferrithiocin to ICL670. Curr. Med. Chem. 10, 1065–1076 (2003).
Porter, J. et al. Health-related quality of life, treatment satisfaction, adherence and persistence in β-thalassemia and myelodysplastic syndrome patients with iron overload receiving deferasirox: results from the EPIC clinical trial. Anemia 2012, e297641 (2012).
Borgna-Pignatti, C. & Marsella, M. Iron chelation in thalassemia major. Clin. Ther. 37, 2866–2877 (2015).
Li, H. et al. Transferrin therapy ameliorates disease in β-thalassemic mice. Nat. Med. 16, 177–182 (2010).
Donfrancesco, A. et al. Effects of a single course of deferoxamine in neuroblastoma patients. Cancer Res. 50, 4929–4930 (1990).
Donfrancesco, A. et al. Deferoxamine followed by cyclophosphamide, etoposide, carboplatin, thiotepa, induction regimen in advanced neuroblastoma: preliminary results. Eur. J. Cancer 31, 612–615 (1995).
Kovacevic, Z., Chikhani, S., Lovejoy, D. B. & Richardson, D. R. Novel thiosemicarbazone iron chelators induce up-regulation and phosphorylation of the metastasis suppressor N-myc down-stream regulated gene 1: a new strategy for the treatment of pancreatic cancer. Mol. Pharmacol. 80, 598–609 (2011).
Lynch, S. G., Peters, K. & LeVine, S. M. Desferrioxamine in chronic progressive multiple sclerosis: a pilot study. Mult. Scler. 2, 157–160 (1996).
McLachlan, D. R. C. et al. Intramuscular desferrioxamine in patients with Alzheimer's disease. Lancet 337, 1304–1308 (1991).
Devos, D. et al. Targeting chelatable iron as a therapeutic modality in Parkinson's disease. Antioxid. Redox Signal. 21, 195–210 (2013).
Preza, G. C. et al. Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. J. Clin. Invest. 121, 4880–4888 (2011).
Casu, C. et al. Minihepcidin peptides as disease modifiers in mice affected by β-thalassemia and polycythemia vera. Blood 128, 265–276 (2016).
Ramos, E. et al. Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis. Blood 120, 3829–3836 (2012).
Vadhan-Raj, S. et al. Phase 1 study of a hepcidin antagonist, LY2787106, in cancer-associated anemia. Blood 126, 537 (2015).
Cooke, K. S. et al. A fully human anti-hepcidin antibody modulates iron metabolism in both mice and nonhuman primates. Blood 122, 3054–3061 (2013).
Hohlbaum, A. et al. Iron mobilization and pharmacodynamic marker measurements in non-human primates following administration of PRS-080, a novel and highly specific anti-hepcidin therapeutic. Am. J. Hematol. 88, E41 (2013).
van Eijk, L. T. et al. Effect of the antihepcidin Spiegelmer lexaptepid on inflammation-induced decrease in serum iron in humans. Blood 124, 2643–2646 (2014).
Boyce, M. et al. Safety, pharmacokinetics and pharmacodynamics of the anti-hepcidin Spiegelmer lexaptepid pegol in healthy subjects. Br. J. Pharmacol. 173, 1580–1588 (2016).
Le Gac, G. et al. Structure–function analysis of the human ferroportin iron exporter (SLC40A1): effect of hemochromatosis type 4 disease mutations and identification of critical residues. Hum. Mutat. 34, 1371–1380 (2013).
Taniguchi, R. et al. Outward- and inward-facing structures of a putative bacterial transition-metal transporter with homology to ferroportin. Nat. Commun. 6, 8545 (2015).
Fernandes, A. et al. The molecular basis of hepcidin-resistant hereditary hemochromatosis. Blood 114, 437–443 (2009).
Fung, E. et al. High-throughput screening of small molecules identifies hepcidin antagonists. Mol. Pharmacol. 83, 681–690 (2013).
Leung, D. et al. LY2928057, an antibody targeting ferroportin, is a potent inhibitor of hepcidin activity and increases iron mobilization in normal cynomolgus monkeys. Blood 122, 3433 (2013).
Andriopoulos, B. Jr et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat. Genet. 41, 482–487 (2009).
Poli, M. et al. Glycol-split nonanticoagulant heparins are inhibitors of hepcidin expression in vitro and in vivo. Blood 123, 1564–1573 (2014).
Yu, P. B. et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat. Chem. Biol. 4, 33–41 (2008).
Cuny, G. D. et al. Structure–activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors. Bioorg. Med. Chem. Lett. 18, 4388–4392 (2008).
Akinc, A. et al. Targeting the hepcidin pathway with RNAi therapeutics for the treatment of anemia. Blood 118, 688 (2011).
Babitt, J. L. et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat. Genet. 38, 531–539 (2006).
Silvestri, L. et al. The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab. 8, 502–511 (2008).
Du, X. et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science 320, 1088–1092 (2008).
Maurer, E. et al. Insights into matriptase-2 substrate binding and inhibition mechanisms by analyzing active-site-mutated variants. ChemMedChem 7, 68–72 (2012).
Sisay, M. T. et al. Identification of the first low-molecular-weight inhibitors of matriptase-2. J. Med. Chem. 53, 5523–5535 (2010).
Guo, S. et al. Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice. J. Clin. Invest. 123, 1531–1541 (2013).
Casu, C. et al. Combination of Tmprss6- ASO and the iron chelator deferiprone improves erythropoiesis and reduces iron overload in a mouse model of beta-thalassemia intermedia. Haematologica 101, e8–e11 (2016).
Schmidt, P. J. et al. An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe−/− mice and ameliorates anemia and iron overload in murine β-thalassemia intermedia. Blood 121, 1200–1208 (2013).
Béliveau, F., Désilets, A. & Leduc, R. Probing the substrate specificities of matriptase, matriptase-2, hepsin and DESC1 with internally quenched fluorescent peptides. FEBS J. 276, 2213–2226 (2009).
Beckmann, A.-M. et al. En route to new therapeutic options for iron overload diseases: matriptase-2 as a target for Kunitz-type inhibitors. ChemBioChem 17, 595–604 (2016).
Zhen, A. W. et al. The small molecule, genistein, increases hepcidin expression in human hepatocytes. Hepatology 58, 1315–1325 (2013).
Chung, B., Matak, P., McKie, A. T. & Sharp, P. Leptin increases the expression of the iron regulatory hormone hepcidin in HuH7 human hepatoma cells. J. Nutr. 137, 2366–2370 (2007).
Zhang, S.-P. AG490: an inhibitor of hepcidin expression in vivo. World J. Gastroenterol. 17, 5032 (2011).
Fatih, N. et al. Natural and synthetic STAT3 inhibitors reduce hepcidin expression in differentiated mouse hepatocytes expressing the active phosphorylated STAT3 form. J. Mol. Med. 88, 477–486 (2010).
Czachorowski, M., Lam- Yuk-Tseung, S., Cellier, M. & Gros, P. Transmembrane topology of the mammalian Slc11a2 iron transporter. Biochemistry 48, 8422–8434 (2009).
Wang, D., Song, Y., Li, J., Wang, C. & Li, F. Structure and metal ion binding of the first transmembrane domain of DMT1. Biochim. Biophys. Acta 1808, 1639–1644 (2011).
Ehrnstorfer, I. A., Geertsma, E. R., Pardon, E., Steyaert, J. & Dutzler, R. Crystal structure of a SLC11 (NRAMP) transporter reveals the basis for transition-metal ion transport. Nat. Struct. Mol. Biol. 21, 990–996 (2014).
Buckett, P. D. & Wessling-Resnick, M. Small molecule inhibitors of divalent metal transporter-1. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G798–G804 (2009).
Horonchik, L. & Wessling-Resnick, M. The small-molecule iron transport inhibitor ferristatin/NSC306711 promotes degradation of the transferrin receptor. Chem. Biol. 15, 647–653 (2008).
Byrne, S. L. et al. Ferristatin II promotes degradation of transferrin receptor-1 in vitro and in vivo. PLoS ONE 8, e70199 (2013).
Yanatori, I., Yasui, Y., Noguchi, Y. & Kishi, F. Inhibition of iron uptake by ferristatin II is exerted through internalization of DMT1 at the plasma membrane. Cell Biol. Int. 39, 427–434 (2015).
Alkhateeb, A. A. et al. The small molecule ferristatin II induces hepatic hepcidin expression in vivo and in vitro. Am. J. Physiol. Gastrointest. Liver Physiol. 308, G1019–G1026 (2015).
International Agency for Research on Cancer in A Review of Human Carcinogens. Part F: Chemical Agents and Related Occupations Vol. 100F 53–64 (World Health Organization, 2012).
Wetli, H. A., Buckett, P. D. & Wessling-Resnick, M. Small-molecule screening identifies the selanazal drug ebselen as a potent inhibitor of DMT1-mediated iron uptake. Chem. Biol. 13, 965–972 (2006).
Davis, M. T. & Bartfay, W. J. Ebselen decreases oxygen free radical production and iron concentrations in the hearts of chronically iron-overloaded mice. Biol. Res. Nurs. 6, 37–45 (2004).
Cadieux, J. A. et al. Synthesis and biological evaluation of substituted pyrazoles as blockers of divalent metal transporter 1 (DMT1). Bioorg. Med. Chem. Lett. 22, 90–95 (2012).
Zhang, Z. et al. Discovery of benzylisothioureas as potent divalent metal transporter 1 (DMT1) inhibitors. Bioorg. Med. Chem. Lett. 22, 5108–5113 (2012).
Montalbetti, N. et al. Discovery and characterization of a novel non-competitive inhibitor of the divalent metal transporter DMT1/SLC11A2. Biochem. Pharmacol. 96, 216–224 (2015).
Span, K. et al. A novel oral iron-complex formulation: encapsulation of hemin in polymeric micelles and its in vitro absorption. Eur. J. Pharm. Biopharm. 108, 226–234 (2016).
Latunde-Dada, G. O. et al. A nanoparticulate ferritin-core mimetic is well taken up by HuTu 80 duodenal cells and its absorption in mice is regulated by body iron. J. Nutr. 144, 1896–1902 (2014).
Taylor, K. M., Morgan, H. E., Johnson, A. & Nicholson, R. I. Structure–function analysis of a novel member of the LIV-1 subfamily of zinc transporters, ZIP14. FEBS Lett. 579, 427–432 (2005).
Peyssonnaux, C. et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J. Clin. Invest. 117, 1926–1932 (2007).
Qian, Z.-M. et al. Divalent metal transporter 1 is a hypoxia-inducible gene. J. Cell. Physiol. 226, 1596–1603 (2011).
Shah, Y. M., Matsubara, T., Ito, S., Yim, S.-H. & Gonzalez, F. J. Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency. Cell Metab. 9, 152–164 (2009).
Tacchini, L., Bianchi, L., Bernelli-Zazzera, A. & Cairo, G. Transferrin receptor induction by hypoxia. HIF-1-mediated transcriptional activation and cell-specific post-transcriptional regulation. J. Biol. Chem. 274, 24142–24146 (1999).
Taylor, M. et al. Hypoxia-inducible factor-2α mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice. Gastroenterology 140, 2044–2055 (2011).
Scheuermann, T. H. et al. Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat. Chem. Biol. 9, 271–276 (2013). This study identifies small molecules that can block HIF2 dimerization and thereby inhibit its function as a transcription factor controlling the expression of numerous genes, including those involved in iron metabolism.
Scheuermann, T. H. et al. Isoform-selective and stereoselective inhibition of hypoxia inducible factor-2. J. Med. Chem. 58, 5930–5941 (2015).
Bruick, R. K. & McKnight, S. L. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294, 1337–1340 (2001).
Epstein, A. C. R. et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107, 43–54 (2001).
McDonough, M. A. et al. Cellular oxygen sensing: crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2). Proc. Natl Acad. Sci. USA 103, 9814–9819 (2006).
Maxwell, P. H. & Eckardt, K.-U. HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond. Nat. Rev. Nephrol. 12, 157–168 (2016).
Barrett, T. D. et al. Prolyl hydroxylase inhibition corrects functional iron deficiency and inflammation-induced anaemia in rats. Br. J. Pharmacol. 172, 4078–4088 (2015). This study is the first to demonstrate the utility of PHD inhibitors in improving iron availability in preclinical models of iron deficiency and AI/ACD.
Rajagopalan, S., Rane, A., Chinta, S. J. & Andersen, J. K. Regulation of ATP13A2 via PHD2-HIF1α signaling is critical for cellular iron homeostasis: implications for Parkinson's disease. J. Neurosci. 36, 1086–1095 (2016).
Provenzano, R. et al. Roxadustat (FG-4592) versus epoetin alfa for anemia in patients receiving maintenance hemodialysis: a phase 2, randomized, 6- to 19-week, open-label, active-comparator, dose-ranging, safety and exploratory efficacy study. Am. J. Kidney Dis. 67, 912–924 (2016).
Brigandi, R. A. et al. A novel hypoxia-inducible factor-prolyl hydroxylase inhibitor (GSK1278863) for anemia in CKD: a 28-day, phase 2A randomized trial. Am. J. Kidney Dis. 67, 861–871 (2016).
Hartman, C. S. et al. AKB-6548, a new hypoxia-inducible factor prolyl hydroxylase inhibitor increases hemoglobin while decreasing ferritin in a 28-day, phase 2a dose escalation study in stage 3 and 4 chronic kidney disease patients with anemia [Abstract]. J. Am. Soc. Nephrol. 22, 435A (2011).
Boettcher, M. F. et al. First-in-man study with BAY 85–3934 — a new oral selective HIF-PH inhibitor for the treatment of renal anemia [abstract]. J. Am. Soc. Nephrol. 24, 347A (2013).
Akizawa, T., Hanaki, K. & Arai, M. JTZ-951, an oral novel Hif-Phd inhibitor, elevates hemoglobin in Japanese anemic patients with chronic kidney disease not on dialysis. Nephrol. Dial. Transplant. 30, iii196 (2015).
Jain, M. et al. Pharmacological characterization of ZYAN1, a novel prolyl hydroxylase inhibitor for the treatment of anemia. Drug Res. 66, 107–112 (2015).
Salvati, A. et al. Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface. Nat. Nanotechnol. 8, 137–143 (2013).
Singh, R. et al. Dose-dependent therapeutic distinction between active and passive targeting revealed using transferrin-coated PGMA nanoparticles. Small 12, 351–359 (2016).
van der Meel, R., Vehmeijer, L. J. C., Kok, R. J., Storm, G. & van Gaal, E. V. B. Ligand-targeted particulate nanomedicines undergoing clinical evaluation: current status. Adv. Drug Deliv. Rev. 65, 1284–1298 (2013).
Senzer, N. et al. Phase I study of a systemically delivered p53 nanoparticle in advanced solid tumors. Mol. Ther. 21, 1096–1103 (2013).
Zhang, H. et al. Transferrin-mediated fullerenes nanoparticles as Fe2+-dependent drug vehicles for synergistic anti-tumor efficacy. Biomaterials 37, 353–366 (2015).
O'Neill, P. M., Barton, V. E. & Ward, S. A. The molecular mechanism of action of artemisinin — the debate continues. Molecules 15, 1705–1721 (2010).
Wiley, D. T., Webster, P., Gale, A. & Davis, M. E. Transcytosis and brain uptake of transferrin-containing nanoparticles by tuning avidity to transferrin receptor. Proc. Natl Acad. Sci. USA 110, 8662–8667 (2013).
Sehlin, D. et al. Antibody-based PET imaging of amyloid beta in mouse models of Alzheimer's disease. Nat. Commun. 7, 10759 (2016).
Jutz, G., van Rijn, P., Santos Miranda, B. & Böker, A. Ferritin: a versatile building block for bionanotechnology. Chem. Rev. 115, 1653–1701 (2015).
Crich, S. G. et al. Targeting ferritin receptors for the selective delivery of imaging and therapeutic agents to breast cancer cells. Nanoscale 7, 6527–6533 (2015).
Lei, Y. et al. Targeted tumor delivery and controlled release of neuronal drugs with ferritin nanoparticles to regulate pancreatic cancer progression. J. Control. Release 232, 131–142 (2016).
Hu, H. et al. The M2 phenotype of tumor-associated macrophages in the stroma confers a poor prognosis in pancreatic cancer. Tumor Biol. 37, 8657–8664 (2016).
Van Gorp, H., Delputte, P. L. & Nauwynck, H. J. Scavenger receptor CD163, a Jack-of-all-trades and potential target for cell-directed therapy. Mol. Immunol. 47, 1650–1660 (2010).
Etzerodt, A. et al. Efficient intracellular drug-targeting of macrophages using stealth liposomes directed to the hemoglobin scavenger receptor CD163. J. Control. Release 160, 72–80 (2012).
Amin, M. L., Kim, D. & Kim, S. Development of hematin conjugated PLGA nanoparticle for selective cancer targeting. Eur. J. Pharm. Sci. 91, 138–143 (2016).
Takle, G. B. et al. Delivery of oligoribonucleotides to human hepatoma cells using cationic lipid particles conjugated to ferric protoporphyrin IX (heme). Antisense Nucleic Acid. Drug Dev. 7, 177–185 (1997).
Kell, D. B. Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases. BMC Med. Genomics 2, 2 (2009).
Nairz, M. et al. 'Ride on the ferrous wheel' — the cycle of iron in macrophages in health and disease. Immunobiology 220, 280–294 (2015).
Ganz, T. & Nemeth, E. Iron homeostasis in host defence and inflammation. Nat. Rev. Immunol. 15, 500–510 (2015).
Miron, V. E. et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat. Neurosci. 16, 1211–1218 (2013).
Biswas, S. K., Chittezhath, M., Shalova, I. N. & Lim, J.-Y. Macrophage polarization and plasticity in health and disease. Immunol. Res. 53, 11–24 (2012).
Bronte, V. & Murray, P. J. Understanding local macrophage phenotypes in disease: modulating macrophage function to treat cancer. Nat. Med. 21, 117–119 (2015).
Crielaard, B. J. et al. Macrophages and liposomes in inflammatory disease: friends or foes? Int. J. Pharm. 416, 499–506 (2011).
Kiessling, F., Mertens, M. E., Grimm, J. & Lammers, T. Nanoparticles for imaging: top or flop? Radiology 273, 10–28 (2014).
Lartigue, L. et al. Biodegradation of iron oxide nanocubes: high-resolution in situ monitoring. ACS Nano 7, 3939–3952 (2013).
Daldrup-Link, H. E. et al. MRI of tumor-associated macrophages with clinically applicable iron oxide nanoparticles. Clin. Cancer Res. 17, 5695–5704 (2011).
Hervault, A. et al. Doxorubicin loaded dual pH- and thermo-responsive magnetic nanocarrier for combined magnetic hyperthermia and targeted controlled drug delivery applications. Nanoscale 8, 12152–12161 (2016).
Xian-hui, D. et al. Age-related changes of brain iron load changes in the frontal cortex in APPswe/PS1ΔE9 transgenic mouse model of Alzheimer's disease. J. Trace Elem. Med. Biol. 30, 118–123 (2015).
Salazar, J. et al. Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson's disease. Proc. Natl Acad. Sci. USA 105, 18578–18583 (2008).
Brookes, M. J. et al. Modulation of iron transport proteins in human colorectal carcinogenesis. Gut 55, 1449–1460 (2006).
Hulet, S. W., Powers, S. & Connor, J. R. Distribution of transferrin and ferritin binding in normal and multiple sclerotic human brains. J. Neurol. Sci. 165, 48–55 (1999).
Li, W., Xu, L.-H., Forssell, C., Sullivan, J. L. & Yuan, X.-M. Overexpression of transferrin receptor and ferritin related to clinical symptoms and destabilization of human carotid plaques. Exp. Biol. Med. 233, 818–826 (2008).
Jefferies, W. A. et al. Reactive microglia specifically associated with amyloid plaques in Alzheimer's disease brain tissue express melanotransferrin. Brain Res. 712, 122–126 (1996).
Kalaria, R. N., Sromek, S. M., Grahovac, I. & Harik, S. I. Transferrin receptors of rat and human brain and cerebral microvessels and their status in Alzheimer's disease. Brain Res. 585, 87–93 (1992).
Faucheux, B. A. et al. Distribution of 125I-ferrotransferrin binding sites in the mesencephalon of control subjects and patients with Parkinson's disease. J. Neurochem. 60, 2338–2341 (1993).
Morris, C. M., Candy, J. M., Omar, S., Bloxham, C. A. & Edwardson, J. A. Transferrin receptors in the parkinsonian midbrain. Neuropathol. Appl. Neurobiol. 20, 468–472 (1994).
Visanji, N. P. et al. Iron deficiency in parkinsonism: region-specific iron dysregulation in Parkinson's disease and multiple system atrophy. J. Park. Dis. 3, 523–537 (2013).
Zhang, Z. et al. Parenchymal accumulation of CD163+ macrophages/microglia in multiple sclerosis brains. J. Neuroimmunol. 237, 73–79 (2011).
Pey, P., Pearce, R. K., Kalaitzakis, M. E., Griffin, W. S. T. & Gentleman, S. M. Phenotypic profile of alternative activation marker CD163 is different in Alzheimer's and Parkinson's disease. Acta Neuropathol. Commun. 2, 21 (2014).
Boyle, J. J. et al. Coronary intraplaque hemorrhage evokes a novel atheroprotective macrophage phenotype. Am. J. Pathol. 174, 1097–1108 (2009).
Tiainen, S. et al. High numbers of macrophages, especially M2-like (CD163-positive), correlate with hyaluronan accumulation and poor outcome in breast cancer. Histopathology 66, 873–883 (2015).
Lundholm, M. et al. Secreted factors from colorectal and prostate cancer cells skew the immune response in opposite directions. Sci. Rep. 5, 15651 (2015).
Mignogna, C. et al. A reappraisal of macrophage polarization in glioblastoma: histopathological and immunohistochemical findings and review of the literature. Pathol. Res. Pract. 212, 491–499 (2016).
LeVine, S. M. Iron deposits in multiple sclerosis and Alzheimer's disease brains. Brain Res. 760, 298–303 (1997).
Connor, J. R., Menzies, S. L., St. Martin, S. M. & Mufson, E. J. A histochemical study of iron, transferrin, and ferritin in Alzheimer's diseased brains. J. Neurosci. Res. 31, 75–83 (1992).
Ji, J. et al. Low expression of ferroxidases is implicated in the iron retention in human atherosclerotic plaques. Biochem. Biophys. Res. Commun. 464, 1134–1138 (2015).
Loeffler, D. A. et al. Transferrin and iron in normal, Alzheimer's disease, and Parkinson's disease brain regions. J. Neurochem. 65, 710–716 (1995).
Galesloot, T. E. et al. Serum hepcidin is associated with presence of plaque in postmenopausal women of a general population. Arterioscler. Thromb. Vasc. Biol. 34, 446–456 (2014).
Orlandi, R. et al. Hepcidin and ferritin blood level as noninvasive tools for predicting breast cancer. Ann. Oncol. 25, 352–357 (2014).
LeVine, S. M. et al. Ferritin, transferrin and iron concentrations in the cerebrospinal fluid of multiple sclerosis patients. Brain Res. 821, 511–515 (1999).
Sato, Y. et al. Cerebrospinal fluid ferritin in glioblastoma: evidence for tumor synthesis. J. Neurooncol. 40, 47–50 (1998).
Sung, K.-C. et al. Ferritin is independently associated with the presence of coronary artery calcium in 12 033 men. Arterioscler. Thromb. Vasc. Biol. 32, 2525–2530 (2012).
Chua, A. C., Knuiman, M. W., Trinder, D., Divitini, M. L. & Olynyk, J. K. Higher concentrations of serum iron and transferrin saturation but not serum ferritin are associated with cancer outcomes. Am. J. Clin. Nutr. 104, 736–742 (2016).
Wang, R., Liu, Z. & Yan, L. Serum iron levels and Parkinson's disease risk: evidence from a meta-analysis. Int. J. Clin. Exp. Med. 9, 3167–3172 (2016).
Valberg, L. S., Flanagan, P. R., Kertesz, A. & Ebers, G. C. Abnormalities in iron metabolism in multiple sclerosis. Can. J. Neurol. Sci. 16, 184–186 (1989).
Faux, N. G. et al. An anemia of Alzheimer's disease. Mol. Psychiatry 19, 1227–1234 (2014).
Hare, D. J. et al. Decreased plasma iron in Alzheimer's disease is due to transferrin desaturation. ACS Chem. Neurosci. 6, 398–402 (2015).
Meynard, D. et al. Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat. Genet. 41, 478–481 (2009).
Feng, Q., Migas, M. C., Waheed, A., Britton, R. S. & Fleming, R. E. Ferritin upregulates hepatic expression of bone morphogenetic protein 6 and hepcidin in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G1397–G1404 (2012).
Rausa, M. et al. Bmp6 expression in murine liver non parenchymal cells: a mechanism to control their high iron exporter activity and protect hepatocytes from iron overload? PLoS ONE 10, e0122696 (2015).
Daher, R. et al. Heterozygous mutations in BMP6 pro-peptide lead to inappropriate hepcidin synthesis and moderate iron overload in humans. Gastroenterology 150, 672–683.e4 (2016).
Kautz, L. et al. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat. Genet. 46, 678–684 (2014). This study identifies erythroferrone, the protein that links erythropoietic activity to suppressed HAMP transcription.
Kautz, L., Jung, G., Nemeth, E. & Ganz, T. Erythroferrone contributes to recovery from anemia of inflammation. Blood 124, 2569–2574 (2014).
Montosi, G. et al. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J. Clin. Invest. 108, 619–623 (2001).
Njajou, O. T. et al. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat. Genet. 28, 213–214 (2001).
Wallace, D. F., Clark, R. M., Harley, H. A. J. & Subramaniam, V. N. Autosomal dominant iron overload due to a novel mutation of ferroportin1 associated with parenchymal iron loading and cirrhosis. J. Hepatol. 40, 710–713 (2004).
Healey, E. G. et al. Repulsive guidance molecule is a structural bridge between neogenin and bone morphogenetic protein. Nat. Struct. Mol. Biol. 22, 458–465 (2015).
Papanikolaou, G. et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat. Genet. 36, 77–82 (2004).
D'Alessio, F., Hentze, M. W. & Muckenthaler, M. U. The hemochromatosis proteins HFE, TfR2, and HJV form a membrane-associated protein complex for hepcidin regulation. J. Hepatol. 57, 1052–1060 (2012).
Roetto, A. et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat. Genet. 33, 21–22 (2003).
Vaiopoulos, G. et al. Arthropathy in juvenile hemochromatosis. Arthritis Rheum. 48, 227–230 (2003).
Feder, J. N. et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat. Genet. 13, 399–408 (1996).
Wallace, D. F. et al. Combined deletion of Hfe and transferrin receptor 2 in mice leads to marked dysregulation of hepcidin and iron overload. Hepatology 50, 1992–2000 (2009).
Latour, C. et al. Differing impact of the deletion of hemochromatosis-associated molecules HFE and transferrin receptor-2 on the iron phenotype of mice lacking bone morphogenetic protein 6 or hemojuvelin. Hepatology 63, 126–137 (2016).
Schmidt, P. J., Toran, P. T., Giannetti, A. M., Bjorkman, P. J. & Andrews, N. C. The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab. 7, 205–214 (2008).
Nemeth, E. et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Invest. 113, 1271–1276 (2004).
Boulanger, M. J., Chow, D., Brevnova, E. E. & Garcia, K. C. Hexameric structure and assembly of the interleukin-6/IL-6 α-receptor/gp130 complex. Science 300, 2101–2104 (2003).
Meynard, D. et al. Regulation of TMPRSS6 by BMP6 and iron in human cells and mice. Blood 118, 747–756 (2011).
Nai, A. et al. Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice. Blood 127, 2327–2336 (2016).
Bell, C. H. et al. Structure of the repulsive guidance molecule (RGM)-neogenin signaling hub. Science 341, 77–80 (2013).
Zhao, N. et al. Neogenin facilitates the induction of hepcidin expression by hemojuvelin in the liver. J. Biol. Chem. 291, 12322–12335 (2016).
Kawabata, H. et al. Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. J. Biol. Chem. 274, 20826–20832 (1999).
Camaschella, C. et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat. Genet. 25, 14–15 (2000).
Pagani, A. et al. Regulation of cell surface transferrin receptor-2 by iron-dependent cleavage and release of a soluble form. Haematologica 100, 458–465 (2015).
Jiang, Y., Oliver, P., Davies, K. E. & Platt, N. Identification and characterization of murine SCARA5, a novel class A scavenger receptor that is expressed by populations of epithelial cells. J. Biol. Chem. 281, 11834–11845 (2006).
Ojala, J. R. M., Pikkarainen, T., Elmberger, G. & Tryggvason, K. Progressive reactive lymphoid connective tissue disease and development of autoantibodies in scavenger receptor A5-deficient mice. Am. J. Pathol. 182, 1681–1695 (2013).
Philippidis, P. et al. Hemoglobin scavenger receptor CD163 mediates interleukin-10 release and heme oxygenase-1 synthesis antiinflammatory monocyte-macrophage responses in vitro, in resolving skin blisters in vivo, and after cardiopulmonary bypass surgery. Circ. Res. 94, 119–126 (2004).
Vargas, J. D. et al. Stromal cell-derived receptor 2 and cytochrome b561 are functional ferric reductases. Biochim. Biophys. Acta 1651, 116–123 (2003).
Gunshin, H. et al. Cybrd1 (duodenal cytochrome b) is not necessary for dietary iron absorption in mice. Blood 106, 2879–2883 (2005).
Choi, J. et al. Duodenal reductase activity and spleen iron stores are reduced and erythropoiesis is abnormal in Dcytb knockout mice exposed to hypoxic conditions. J. Nutr. 142, 1929–1934 (2012).
Gunshin, H. et al. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J. Clin. Invest. 115, 1258–1266 (2005).
Kvarnung, M. et al. Mutations in FLVCR2 associated with Fowler syndrome and survival beyond infancy. Clin. Genet. 89, 99–103 (2016).
Delaby, C. et al. Subcellular localization of iron and heme metabolism related proteins at early stages of erythrophagocytosis. PLoS ONE 7, e42199 (2012).
Herz, J., Clouthier, D. E. & Hammer, R. E. LDL receptor-related protein internalizes and degrades uPA-PAI-1 complexes and is essential for embryo implantation. Cell 71, 411–421 (1992).
Overton, C. D., Yancey, P. G., Major, A. S., Linton, M. F. & Fazio, S. Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse. Circ. Res. 100, 670–677 (2007).
Gomes, I. M., Maia, C. J. & Santos, C. R. STEAP proteins: from structure to applications in cancer therapy. Mol. Cancer Res. 10, 573–587 (2012).
Grandchamp, B. et al. A novel type of congenital hypochromic anemia associated with a nonsense mutation in the STEAP3/TSAP6 gene. Blood 118, 6660–6666 (2011).
Liu, D. et al. Human STEAP3 mutations with no phenotypic red cell changes. Blood 127, 1067–1071 (2016).
Knisely, A. S., Gelbart, T. & Beutler, E. Molecular characterization of a third case of human atransferrinemia. Blood 104, 2607 (2004).
Levy, J. E., Jin, O., Fujiwara, Y., Kuo, F. & Andrews, N. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat. Genet. 21, 396–399 (1999).
Hojyo, S. et al. The zinc transporter SLC39A14/ZIP14 controls G-protein coupled receptor-mediated signaling required for systemic growth. PLoS ONE 6, e18059 (2011).
Ji, C. & Kosman, D. J. Molecular mechanisms of non-transferrin-bound and transferring-bound iron uptake in primary hippocampal neurons. J. Neurochem. 133, 668–683 (2015).
Cozzi, A. et al. Human L-ferritin deficiency is characterized by idiopathic generalized seizures and atypical restless leg syndrome. J. Exp. Med. 210, 1779–1791 (2013).
Poss, K. D. & Tonegawa, S. Heme oxygenase 1 is required for mammalian iron reutilization. Proc. Natl Acad. Sci. USA 94, 10919–10924 (1997).
Kovtunovych, G., Eckhaus, M. A., Ghosh, M. C., Ollivierre-Wilson, H. & Rouault, T. A. Dysfunction of the heme recycling system in heme oxygenase 1-deficient mice: effects on macrophage viability and tissue iron distribution. Blood 116, 6054–6062 (2010).
Kawashima, A., Oda, Y., Yachie, A., Koizumi, S. & Nakanishi, I. Heme oxygenase-1 deficiency: the first autopsy case. Hum. Pathol. 33, 125–130 (2002).
Scortegagna, M. et al. Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1−/− mice. Nat. Genet. 35, 331–340 (2003).
Zhuang, Z. et al. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N. Engl. J. Med. 367, 922–930 (2012).
Sanchez, M., Galy, B., Muckenthaler, M. U. & Hentze, M. W. Iron-regulatory proteins limit hypoxia-inducible factor-2α expression in iron deficiency. Nat. Struct. Mol. Biol. 14, 420–426 (2007).
Troadec, M.-B. et al. Targeted deletion of the mouse Mitoferrin1 gene: from anemia to protoporphyria. Blood 117, 5494–5502 (2011).
Percy, M. J. et al. A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc. Natl Acad. Sci. USA 103, 654–659 (2006).
Takeda, K. et al. Placental but not heart defects are associated with elevated hypoxia-inducible factor α levels in mice lacking prolyl hydroxylase domain protein 2. Mol. Cell. Biol. 26, 8336–8346 (2006).
Kono, S. Aceruloplasminemia. Curr. Drug Targets 13, 1190–1199 (2012).
Quigley, J. G. et al. Identification of a human heme exporter that is essential for erythropoiesis. Cell 118, 757–766 (2004).
Byon, J. C. H., Chen, J., Doty, R. T. & Abkowitz, J. L. FLVCR is necessary for erythroid maturation, may contribute to platelet maturation, but is dispensable for normal hematopoietic stem cell function. Blood 122, 2903–2910 (2013).
Chiabrando, D. et al. The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation. J. Clin. Invest. 122, 4569–4579 (2012).
Rey, M. A. et al. Enhanced alternative splicing of the FLVCR1 gene in Diamond Blackfan anemia disrupts FLVCR1 expression and function that are critical for erythropoiesis. Haematologica 93, 1617–1626 (2008).
Philip, M. et al. Heme exporter FLVCR is required for T cell development and peripheral survival. J. Immunol. 194, 1677–1685 (2015).
Vulpe, C. D. et al. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat. Genet. 21, 195–199 (1999).
Griffiths, T. A. M., Mauk, A. G. & MacGillivray, R. T. A. Recombinant expression and functional characterization of human hephaestin: a multicopper oxidase with ferroxidase activity. Biochemistry 44, 14725–14731 (2005).
Hudson, D. M. et al. Human hephaestin expression is not limited to enterocytes of the gastrointestinal tract but is also found in the antrum, the enteric nervous system, and pancreatic β-cells. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G425–G432 (2010).
Acknowledgements
The authors express their gratitude to K. Römhild for her assistance in the literature review. The authors' work is supported by the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska–Curie grant agreement No 707229 (ADHERE) to B.J.C, the German Research Foundation (DFG: La2937/1-2 to T.L), the European Research Council (ERC: StG-309495, PoC-680882 to T.L), and the US National Institutes of Health grants R01 DK095112 and R01DK090554 to S.R.
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S.R. has restricted stocks in, is a consultant for and a member of the scientific advisory board of Merganser Biotech. S.R. is also a consultant for Novartis Pharmaceuticals, Bayer Healthcare, and Keryx Biopharmaceuticals, and is a member of the scientific advisory board of Ionis Pharmaceuticals. T.L. is a member of the scientific advisory board of Cristal Therapeutics. B.J.C. declares no competing interests.
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FURTHER INFORMATION
Glossary
- Microcytic, hypochromic anaemia
-
Low systemic haemoglobin levels associated with a reduced haemoglobin concentration inside each red blood cell, making them small (microcytic) and pale (hypochromic). This condition is most commonly caused by iron deficiency, but is also found in patients with red blood cell disorders such as thalassaemia.
- Haemochromatosis
-
A family of hereditary diseases that are characterized by genetic mutations affecting an iron metabolism-regulating protein and resulting in excessive iron absorption. As there is no physiological mechanism for iron excretion, iron overload will eventually occur.
- Anticalin
-
Technology developed by Pieris Pharmaceuticals that modifies lipocalins, which are natural extracellular proteins that bind to and transport a variety of ligands, to make therapeutics that target a specific molecule.
- Spiegelmer
-
Technology developed by NOXXON Pharma that uses L-RNA aptamers as therapeutic agents that bind a specific molecule. L-RNA, the stereoisomeric form of physiological d-RNA, is not sensitive to nuclease activity and therefore has improved biological stability.
- Kunitz domain
-
Or Kunitz-type protease inhibitor domain, is the active domain of various protease inhibitors. Their relatively short peptide sequence of ~60 amino acids makes them an interesting lead for the development new biopharmaceutical protease inhibitors.
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Crielaard, B., Lammers, T. & Rivella, S. Targeting iron metabolism in drug discovery and delivery. Nat Rev Drug Discov 16, 400–423 (2017). https://doi.org/10.1038/nrd.2016.248
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DOI: https://doi.org/10.1038/nrd.2016.248
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