Page 13 - 2019_06-Haematologica-web

Editorials
ured but could provide insight into the contribution of anemia to the blunted hepcidin response. It would be interesting to see if iron deficiency alone is sufficient to prevent hepcidin induction following acute inflammatory stimulation. In fact, eight of the 25 women in the non- anemic group were reported to be iron-deficient, but were not analyzed as a subgroup to determine the contri- bution of anemia versus iron deficiency.
In addition to the convergence of signals onto the hep- cidin promoter, another aspect to consider in the regula- tion of hepcidin is the relative strength and duration of each signal. In this study, iron-deficiency anemia was rel- atively mild (median hemoglobin of 11.3 g/dL), but likely chronic. The inflammatory signal was moderate and like- ly transient, with IL-6 increasing approximately 2-3-fold after vaccination compared to baseline. Hepcidin induc- tion was similarly moderate: in the non-anemic group, hepcidin levels increased 2-fold by 24 h compared to baseline. Whether a stronger or more prolonged inflam- matory stimulus, such as during an active infection, would over-ride the effect of IDA on hepcidin remains to be determined. Nevertheless, in agreement with Stoffel et al., a cross-sectional study that compared patients with anemia of chronic disease (ACD) to those with IDA or mixed ACD/IDA condition, reported that hepcidin was increased in patients with ACD compared to control sub- jects, but that in patients with mixed ACD/IDA, despite elevated IL-6, hepcidin levels were comparable to those observed in IDA patients.24
In conclusion, the data obtained from the well- designed and well-executed prospective study in human subjects by Stoffel et al. support the conclusion that dur- ing iron-deficiency anemia, when challenged by moder- ate but transient acute inflammation, iron acquisition is prioritized over iron restriction. The questions about the molecular mechanism and relative contribution of ery- thropoietic activity versus iron deficiency in preventing an inflammation-mediated increase in hepcidin still have to be answered. Importantly, this human study pioneers the analysis of the interactions of iron deficiency and inflam- mation, a subject of great importance for designing and implementing policies to prevent and treat anemia in regions where iron deficiency, infection and inflamma- tion are all too common.
Acknowledgments and disclosures
Sources of support: NIH Ruth L. Kirschstein National Research Service Award T32-5T32HL072752-13 (to VS). EN is a shareholder and scientific advisor of Intrinsic LifeSciences.
References
1. Ganz T. Systemic iron homeostasis. Physiol Rev. 2013;93(4):1721- 1741.
2. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization.
Science. 2004;306(5704):2090-2093.
3. Sangkhae V, Nemeth E. Regulation of the Iron Homeostatic
Hormone Hepcidin. Adv Nutr. 2017;8(1):126-136.
4. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron
regulatory peptide hepcidin is regulated by anemia, hypoxia, and
inflammation. J Clin Invest. 2002;110(7):1037-1044.
5. Cassat JE, Skaar EP. Iron in infection and immunity. Cell Host
Microbe. 2013;13(5):509-519.
6. Arezes J, Jung G, Gabayan V, et al. Hepcidin-induced hypoferremia
is a critical host defense mechanism against the siderophilic bacteri-
um Vibrio vulnificus. Cell Host Microbe. 2015;17(1):47-57.
7. Stoffel NU, Lazrak M, Bellitir S, et al. The opposing effects of acute inflammation and iron deficiency anemia on serum hepcidin and iron absorption in young women. Haematologica. 2019;104(6):1143-
1149.
8. Marx JJ, Dinant HJ. Ferrokinetics and red cell iron uptake in old age:
evidence for increased liver iron retention? Haematologica.
1982;67(2):161-168.
9. Marx JJ. Normal iron absorption and decreased red cell iron uptake
in the aged. Blood. 1979;53(2):204-211.
10. ChastonT,ChungB,MascarenhasM,etal.Evidencefordifferential
effects of hepcidin in macrophages and intestinal epithelial cells.
Gut. 2008;57(3):374-382.
11. TruksaJ,LeeP,BeutlerE.TwoBMPresponsiveelements,STAT,and
bZIP/HNF4/COUP motifs of the hepcidin promoter are critical for
BMP, SMAD1, and HJV responsiveness. Blood. 2009;113(3):688-695. 12. CanaliS,Zumbrennen-BulloughKB,CoreAB,etal.Endothelialcells produce bone morphogenetic protein 6 required for iron homeosta-
sis in mice. Blood. 2017;129(4):405-414.
13. Koch PS, Olsavszky V, Ulbrich F, et al. Angiocrine Bmp2 signaling in
murine liver controls normal iron homeostasis. Blood.
2017;129(4):415-419.
14. NemethE,RiveraS,GabayanV,etal.IL-6mediateshypoferremiaof
inflammation by inducing the synthesis of the iron regulatory hor-
mone hepcidin. J Clin Invest. 2004;113(9):1271-1276.
15. Verga Falzacappa MV, Casanovas G, Hentze MW, Muckenthaler MU. A bone morphogenetic protein (BMP)-responsive element in the hepcidin promoter controls HFE2-mediated hepatic hepcidin expression and its response to IL-6 in cultured cells. J Mol Med.
2008;86(5):531-540.
16. WallaceDF,McDonaldCJ,OstiniL,SubramaniamVN.Bluntedhep-
cidin response to inflammation in the absence of Hfe and transferrin
receptor 2. Blood. 2011;117(10):2960-2966.
17. Fillebeen C, Wilkinson N, Charlebois E, Katsarou A, Wagner J,
Pantopoulos K. Hepcidin-mediated hypoferremic response to acute inflammation requires a threshold of Bmp6/Hjv/Smad signaling. Blood. 2018;132(17):1829-1841.
18. Huang H, Constante M, Layoun A, Santos MM. Contribution of STAT3 and SMAD4 pathways to the regulation of hepcidin by opposing stimuli. Blood. 2009;113(15):3593-3599.
19. Steinbicker AU, Sachidanandan C, Vonner AJ, et al. Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation. Blood. 2011;117(18):4915-4923.
20. Mayeur C, Lohmeyer LK, Leyton P, et al. The type I BMP receptor Alk3 is required for the induction of hepatic hepcidin gene expres- sion by interleukin-6. Blood. 2014;123(14):2261-2268.
21. Haase VH. Regulation of erythropoiesis by hypoxia-inducible fac- tors. Blood Rev. 2013;27(1):41-53.
22. Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nature Genet. 2014;46(7):678-684.
23. ArezesJ,FoyN,McHughK,etal.Erythroferroneinhibitstheinduc- tion of hepcidin by BMP6. Blood. 2018;132(14):1473-1477.
24. TheurlI,AignerE,TheurlM,etal.Regulationofironhomeostasisin anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood. 2009;113(21):5277-5286.
haematologica | 2019; 104(6)
1095