Page 11 - 2019_06-Haematologica-web

To induce or not to induce: the fight over hepcidin regulation
Veena Sangkhae and Elizabeta Nemeth
Center for Iron Disorders, David Geffen School of Medicine, University of California, Los Angeles, CA, USA E-mail: NEMETH ELIZABETA - enemeth@mednet.ucla.edu
doi:10.3324/haematol.2019.216960
Systemic iron homeostasis is co-ordinated by the hepatic hormone hepcidin.1 Hepcidin inhibits iron export through the cellular iron transporter ferroportin, there- by preventing iron absorption and the release of recycled or stored iron into plasma, resulting in decreased plasma iron levels.2 Hepcidin production changes rapidly and over a large dynamic range to ensure the maintenance of iron homeosta- sis. Hepcidin is suppressed in conditions that require increased iron supply, such as stress erythropoiesis, hypoxia, growth and pregnancy.3,4 Conversely, hepcidin is induced by iron loading to prevent the accumulation of excess iron, or by inflammation as part of the host defense response to infection.5,6 Although the regulation of hepcidin by singular stimuli has been well studied, particularly in animal models, we still do not have an understanding of the complex inter- play of opposing signals in regulating hepcidin expression and iron homeostasis in humans.
In this issue of Haematologica, Stoffel et al. report on a prospective study in young women to evaluate the relative contribution of iron deficiency anemia and acute inflamma- tory stimulus on iron homeostasis7 (Figure 1). The well-con- trolled study included a total of 46 women: 25 non-anemic and 21 with iron-deficiency anemia (IDA). Compared to their non-anemic counterparts, anemic women had 2 g/dL lower hemoglobin, lower serum iron, transferrin saturation, ferritin and body iron stores, and higher erythropoietin and serum transferrin receptor. The study excluded subjects with confounding factors affecting iron metabolism, including pre-existing inflammation, chronic disease, obesity, pregnan- cy, or vitamin and/or mineral supplementation for two weeks prior to and during the study. An acute inflammatory stimulus was modeled using an intramuscular injection of an influenza/diphtheria-tetanus-pertussis vaccine in all subjects. Inflammatory and iron markers were measured at baseline and 8, 24 and 36 hours (h) post vaccination.
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The subjects also received test meals containing Fe (non-
radioactive isotope of iron), that allowed assessment of ery- throcyte 57Fe incorporation as a measure of iron absorption. The first 57Fe meal and the first erythrocyte 57Fe measure- ment were completed before the inflammatory stimulus (“baseline”). The second 57Fe meal was administered 24 h after the vaccine, at the time of maximal or near-maximal IL- 6 and hepcidin increase, followed by the second erythrocyte 57Fe measurement [“post-vaccine” (Figure 1)]. Although the erythrocyte 57Fe measurements were performed 19 days after each ingestion of 57Fe, they should closely reflect iron absorption on the day of the meal consumption for the fol- lowing reasons. In humans who are not iron-loaded, the majority of the absorbed iron is loaded onto transferrin and is destined for erythropoiesis: ferrokinetics experiments showed that following the ingestion of 59Fe, approximately 82-91% of absorbed radiolabeled iron is detected in erythro- cytes after two weeks.8,9 Furthermore, erythrocyte lifespan is around 120 days, much longer than the duration of the
Stoffel et al. study. Thus, any confounding effect of 57Fe-red blood cell recycling and hepcidin modulation of the recycled iron flows would have been minimal.
Administration of the vaccine induced systemic inflamma- tion in both cohorts of women, as reflected by an increase in interleukin-6 (IL-6), a major regulator of hepcidin produc- tion. Despite this, there was a surprising difference in the hepcidin response. Serum hepcidin increased in the non-ane- mic group within 24 h after vaccination but was unchanged in the IDA group. IL-6 and hepcidin significantly correlated at 24 h after vaccination only in the non-anemic but not in the IDA group. Serum iron levels mirrored the hepcidin response: in the non-anemic cohort, increased serum hep- cidin was associated with decreased serum iron, whereas in the IDA group, no change in serum iron was observed. The authors therefore concluded that during IDA, regulation of hepcidin by iron and/or erythropoietic activity supersedes hepcidin regulation by acute inflammation. Measurement of erythrocyte iron incorporation from 57Fe-labeled test meals provided a valuable insight into iron absorption before and after the acute inflammatory stimulus. Erythrocyte iron incorporation was higher in IDA compared to non-anemic subjects at all time points examined, reflecting increased iron absorption in this group. Interestingly, erythrocyte 57Fe incor- poration was not affected by inflammation in either group, despite increased hepcidin in the non-anemic women. As the authors point out, a possible explanation is that entero- cytes may be less sensitive to the effect of hepcidin than recycling macrophages.10 Thus, a moderate increase in hep- cidin after vaccination in non-anemic women could cause hypoferremia without, at the same time, affecting duodenal 57Fe absorption, because serum iron concentration is pre- dominantly determined by macrophage iron export. Interestingly, in the non-anemic group, erythrocyte 57Fe incorporation was inversely correlated with serum hepcidin both at baseline (r=‒0.792; P<0.001) and after vaccination (r=‒0.708; P<0.001). This suggests that, over a broader range of concentrations, hepcidin does modulate iron absorption, but that hepcidin changes after the vaccination were too small to exert an effect on enterocytes.
This study is the first to test the dynamic hierarchical reg- ulation of hepcidin by iron and inflammation in a well-con- trolled trial in humans, and showed that iron-deficiency ane- mia exerted a dominant effect over that of acute inflamma- tion in this setting. What is the molecular mechanism that could explain this observation? The hepcidin promoter con- tains both bone morphogenetic protein (BMP)-response ele- ments (RE) and a STAT3-RE.11 Iron-mediated hepcidin regu- lation occurs via the BMP-SMAD pathway. It is thought that liver sinusoidal endothelial cells secrete BMP2 and BMP6 in proportion to the liver iron stores;12,13 these ligands then act in a paracrine fashion, and bind BMP receptors and their co- receptor hemojuvelin (HJV) on hepatocytes to induce phos- phorylation of SMAD1/5. Phosphorylated SMAD1/5 form a
haematologica | 2019; 104(6)
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