Maternal hepcidin: the only player on the field?

In this issue of Blood, Sangkhae et al¹  use murine model systems and hepcidin analogs to offer valuable new insights into the central role of maternal hepcidin in determining fetal iron status, the deleterious consequences of its elevation during pregnancy, and its potential relevance in the setting of inflammation. Iron deficiency during pregnancy is prevalent and associated with negative outcomes for both mother and fetus. Inflammation during pregnancy is also common, often subclinical, and associated with adverse outcomes. Profound changes in iron homeostasis occur with systemic inflammation in other settings, many of these being consequent to the increased production of the hormone hepcidin. Investigating the effects of inflammation on iron homeostasis during pregnancy has been challenged by the complex interplay between maternal, placental, and fetal regulatory processes.

Pregnancy is normally a very low hepcidin state in both mother and fetus, thereby optimizing plasma iron availability for expanding fetal needs. The investigators used mice in which hepcidin was knocked out in either the mother or the fetus and determined that maternal rather than fetal or placental hepcidin determines fetal iron status. Loss of maternal hepcidin increased iron delivery to placenta and fetus; loss of fetal hepcidin had no significant effect on measured iron parameters in mother or fetus. The mechanisms by which pregnancy suppresses maternal hepcidin remain to be determined but are of great interest as elucidation may uncover new molecules and/or pathways that can be used therapeutically. The basis for the very low expression of liver fetal hepcidin (compared with postnatal timeframes) is likewise unknown. Plausibly, the hypoxic environment and consequent high erythropoietin levels contribute. Erythroferrone, an erythroid suppressor of hepcidin,²  is upregulated by erythropoietin. Because liver is the primary site of fetal erythropoiesis, local production of erythroferrone may be important. A fetal regulatory circuit presumably exists that allows the fetus to convey increased iron needs in settings of excessive fetal erythropoiesis or multiparous pregnancies.

The investigators next examine whether maternal hepcidin is in excess in pregnancies complicated by inflammation. They determine that systemic inflammation (lipopolysaccharide injection) overcomes the factors that suppress maternal hepcidin. To specifically parse out the effect of hepcidin on maternal-fetal iron metabolism, they administered minihepcidins to uninflamed pregnant dams (see figure). In a high-dose regimen, minihepcidin treatment decreased maternal serum and hepatic iron, increased splenic iron, and caused anemia. At the highest-dose regimen, the effect was severe enough to decrease placental iron and weight, despite compensatory “selfish placenta”³  increases in transferrin receptor 1 (increasing iron uptake from the mother), and decreases in ferroportin (withholding iron transfer to the fetus). The consequences to the fetus in this setting were severe, leading to demise. A shorter-duration regimen did not decrease placental iron and led to decreased fetal serum, liver, and brain iron concentrations and fetal anemia. Similar changes of smaller magnitude were seen at a lower-dose regimen that did not significantly affect maternal iron parameters or hemoglobin. If relevant to the human situation, such observations suggest that the fetus might be sensitive to maternal elevations in hepcidin not apparent in routine screening tests for maternal iron status. Because inflammation during pregnancy is often subclinical, it is important in studies on iron metabolism during pregnancy to assess maternal hepcidin-mediated effects.⁴  Moreover, because ferritin is an acute phase protein, using maternal or cord ferritin levels in assessing iron status might be confounded despite the absence of clinical inflammation.

It is important to emphasize that hepcidin excess is not the only mediator of the changes in iron metabolism with inflammation. Ceruloplasmin, transferrin, and ferritin are each regulated by inflammatory signals.⁵  Inflammation also suppresses erythropoiesis, and thus iron utilization, by mechanisms that are not entirely hepcidin dependent. As such, the minihepcidin experimental systems used by Sangkhae et al would not be expected to completely model iron metabolism during inflammation. They do, nonetheless, raise the possibility that elevated maternal hepcidin contributes to negative outcomes with inflammation during pregnancy.

The investigators’ studies clearly show the deleterious consequences of elevated maternal hepcidin on fetal iron status. Do elevations in fetal hepcidin have any contribution? As pointed out by the authors, increases in fetal hepcidin have been shown to affect fetal iron status in certain experimental systems, including inflammation. Administration of lipopolysaccharide to pregnant mice increased fetal liver hepcidin production, in association with decreased fetal serum iron.⁶  Intraamniotic injection of lipopolysaccharide in rhesus macaques had similar effects, and without increased maternal cytokines or maternal hepcidin.⁶  Suggesting that these observations are relevant to humans, cord blood hepcidin levels were found to be elevated in preterm infants in the setting of chorioamnionitis. The fetal inflammatory response⁷  is an area of intense recent interest, as it is associated with multiple negative postnatal outcomes, including altered immune function.⁸  Whether these are mediated in part by changes in iron metabolism remains speculative.

Very recent data support not just a pathologic but also a physiologic role for fetal hepcidin. Fetal hepatocellular-specific knockout of hepcidin was found to increase ferroportin and decrease iron in the fetal liver.⁹  Minimal, if any, effects were observed on placental ferroportin. These data support an autocrine, but no major hormonal, role for fetal hepatocellular hepcidin under physiologic conditions. Interestingly, blood hemoglobin concentrations were decreased in these fetuses.⁹  The mechanism is unclear, but possibly hepatocellular hepcidin exerts a paracrine effect on local erythroid progenitors. Ferroportin is expressed in the erythroid lineage where it regulates iron efflux.¹⁰  Further supporting this possibility is the observation that while knockin of a hepcidin-resistant ferroportin in fetal hepatocytes decreased liver iron, the effects on hemoglobin were comparatively minor.

These murine model systems identify maternal hepcidin as the “heavy hitter” determining fetal iron status (even if by being largely benched). However, fetal hepcidin is also in the game (even if not playing by the usual rules).