Page 35 - 2020_02-Haematologica-web

Hepcidin and iron disorders
nanoparticles to target intestinal absorption,127 established a proof of principle of reducing dietary iron uptake. Another approach might be to block intestinal HIF-2α by specific antagonists.
Clinical trials are showing that correcting ineffective erythropoiesis by activin ligand traps128 not only improves anemia but, in the long-term, also iron loading in both non-transfusion-dependent and transfusion-dependent thalassemia129 and ringed sideroblast myelodysplastic syn- drome.130 Some thiazolidinones have been shown to stim- ulate hepcidin activity in preclinical studies.131 The use of proton pump inhibitors reduced the need for phlebotomy in patients with hemochromatosis.132
Decreasing hepcidin levels/increasing ferroportin function
In preclinical models of anemia of inflammation, hep- cidin antagonists decreased hepcidin expression, an effect verified in clinical trials for some compounds.133 Another option is to interfere with the hepcidin-ferroportin inter- action (Table 2). However, targeting the hepcidin-ferro- portin axis may not fully correct this multifactorial anemia characterized by low erythropoietin and a blunted ery- thropoietic response.97,98 Another approach is based on manipulation of the hypoxia-responsive pathway.63 Prolyl hydroxylase inhibitors or HIF stabilizers, now tested in chronic kidney disease, by increasing HIF-2α might target two abnormal processes enhancing both erythropoietin synthesis and iron absorption.134
Unresolved issues
Notwithstanding significant advances many questions about iron metabolism and homeostasis remain unan-
swered. The mechanisms of intestinal heme absorption are mysterious, as are the roles of secreted ferritin and sol- uble transferrin receptor. We have just started exploring the autonomous regulation of iron in the heart and vascu- lar wall; the role of iron (deficiency or excess) as a cofactor of metabolic disorders, chronic liver disease, heart failure, pulmonary hypertension and neurodegeneration still requires elucidation. We need to be able to diagnose iso- lated tissue iron deficiency better and to increase the lim- ited number of iron status markers.
In hematology we need to clarify the relationship between iron and platelet production considering that iron deficiency directs the common erythroid-megakaryocyte precursor towards the platelet lineage.135 More informa- tion is required on the role of iron in B-lymphocyte devel- opment and function, in B-cell malignancies, such as mul- tiple myeloma,136 and in response to infectious diseases. We have to explore better how iron/TFR2 intersects the erythropoietin signaling pathway and bone metabolism.
We need novel protocols of iron supplementation and clear indications regarding high-dose intravenous iron to optimize iron therapy. Targeted approaches, now in clin- ical trials, have the potential to change traditional treat- ment – such as the time-honored phlebotomy-based reg- imen – for disorders such as hemochromatosis. Repurposing commercially available compounds, devel- oped for other conditions, to iron/erythroid disorders is another option. All these approaches will, it is hoped, enable a more personalized treatment of iron disorders in the near future.
Acknowledgments
This work was supported in part by an ASH Global Research Award 2017 to AN.
References
1. Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of Mammalian iron metabolism. Cell. 2010;142(1):24-38.
2. Muckenthaler MU, Rivella S, Hentze MW, Galy B. A red carpet for iron metabolism. Cell. 2017;168(3):344-361.
3. Wang CY, Babitt JL. Liver iron sensing and body iron homeostasis. Blood. 2019;133(1): 18-29.
4. BarrientosT,LaothamatasI,KovesTR,etal. Metabolic catastrophe in mice lacking trans- ferrin receptor in muscle. EBioMedicine. 2015;2(11):1705-1717.
5. JabaraHH,BoydenSE,ChouJ,etal.Amis- sense mutation in TFRC, encoding transfer- rin receptor 1, causes combined immunode- ficiency. Nat Genet. 2016;48(1):74-78.
6. Chen AC, Donovan A, Ned-Sykes R, Andrews NC. Noncanonical role of transfer- rin receptor 1 is essential for intestinal home- ostasis. Proc Natl Acad Sci U S A. 2015;112(37):11714-11719.
7. Fillebeen C, Charlebois E, Wagner J, et al. Transferrin receptor 1 controls systemic iron homeostasis by fine-tuning hepcidin expres- sion to hepatocellular iron load. Blood. 2019;133(4):344-355.
8. Kawabata H, Yang R, Hirama T, et al.
Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor- like family. J Biol Chem. 1999;274(30): 20826-20832.
9. Camaschella C, Pagani A, Nai A, Silvestri L. The mutual control of iron and erythro- poiesis. Int J Lab Hematol. 2016;38 (Suppl 1):20-26.
10. Forejtnikova H, Vieillevoye M, Zermati Y, et al. Transferrin receptor 2 is a component of the erythropoietin receptor complex and is required for efficient erythropoiesis. Blood. 2010;116(24):5357-5367.
11. Parrow NL, Li Y, Feola M, et al. Lobe speci- ficity of iron-binding to transferrin modu- lates murine erythropoiesis and iron home- ostasis. Blood. 2019;134(17):1373-1384.
12. Yachie A, Niida Y, Wada T, et al. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficien- cy. J Clin Invest. 1999;103(1):129-135.
13. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its inter- nalization. Science. 2004;306(5704):2090- 2093.
14. Lill R, Broderick JB, Dean DR. Special issue on iron-sulfur proteins: Structure, function, biogenesis and diseases. Biochim Biophys Acta. 2015;1853(6):1251-1252.
15. Braymer JJ, Lill R. Iron-sulfur cluster biogen- esis and trafficking in mitochondria. J Biol Chem. 2017;292(31):12754-12763.
16. Hamdi A, Roshan TM, Kahawita TM, Mason AB, Sheftel AD, Ponka P. Erythroid cell mitochondria receive endosomal iron by a "kiss-and-run" mechanism. Biochim Biophys Acta. 2016;1863(12):2859-2867.
17. Shaw GC, Cope JJ, Li L, et al. Mitoferrin is essential for erythroid iron assimilation. Nature. 2006;440(7080):96-100.
18. Arosio P, Carmona F, Gozzelino R, Maccarinelli F, Poli M. The importance of eukaryotic ferritins in iron handling and cytoprotection. Biochem J. 2015;472(1):1-15.
19. Vanoaica L, Darshan D, Richman L, Schumann K, Kuhn LC. Intestinal ferritin H is required for an accurate control of iron absorption. Cell Metab. 2010;12(3):273-282.
20. Castiglioni E, Soriani N, Girelli D, et al. High resolution melting for the identification of mutations in the iron responsive element of the ferritin light chain gene. Clin Chem Lab Med. 2010;48(10):1415-1418.
21. Luscieti S, Santambrogio P, Langlois d'Estaintot B, et al. Mutant ferritin L-chains that cause neurodegeneration act in a domi- nant-negative manner to reduce ferritin iron incorporation. J Biol Chem. 2010;285(16): 11948-11957.
22. Truman-Rosentsvit M, Berenbaum D, Spektor L, et al. Ferritin is secreted via 2 dis- tinct nonclassical vesicular pathways. Blood. 2018;131(3):342-352.
23. Leidgens S, Bullough KZ, Shi H, et al. Each member of the poly-r(C)-binding protein 1
haematologica | 2020; 105(2)
269