SUMMARY Nearly all forms of hereditary hemochromatosis are characterized by pathological iron accumulation in the liver, pancreas, and heart. These tissues preferentially load iron because they take up non-transferrin-bound iron (NTBI), which appears in the plasma during iron overload. Yet, how tissues take up NTBI is largely unknown. We report that ablation of Slc39a14, the gene coding for solute carrier SLC39A14 (also called ZIP14), in mice markedly reduced the uptake of plasma NTBI by the liver and pancreas. To test the role of SLC39A14 in tissue iron loading, we crossed Slc39a14−/− mice with Hfe−/− and Hfe2−/− mice, animal models of type 1 and type 2 (juvenile) hemochromatosis respectively. Slc39a14 deficiency in hemochromatotic mice greatly diminished iron loading of the liver and prevented iron deposition in hepatocytes and pancreatic acinar cells. The data suggest that inhibition of SLC39A14 may mitigate hepatic and pancreatic iron loading and associated pathologies in iron overload disorders.

The regulation of iron metabolism in biological systems centers on providing adequate iron for cellular function while limiting iron toxicity. Because mammals cannot excrete iron, mechanisms have evolved to control iron acquisition, storage, and distribution at both systemic and cellular levels. Hepcidin, the master regulator of iron homeostasis, controls iron flows into plasma through inhibition of the only known mammalian cellular iron exporter ferroportin. Hepcidin is feedback-regulated by iron status and strongly modulated by inflammation and erythropoietic demand. This review highlights recent advances that have changed our understanding of iron metabolism and its regulation.

Airway mucus is a complex mixture of secretory products that provides a multifaceted defense against pulmonary infection. Mucus contains antimicrobial peptides (e.g., defensins) and enzymes (e.g., lysozyme) although the contribution of these to airway sterility has not been tested in vivo. We have previously shown that an enzymatically active, heme-containing peroxidase comprises 1% of the soluble protein in sheep airway secretions, and it has been hypothesized that this airway peroxidase may function as a biocidal system. In this study, we show that sheep airway peroxidase is identical to milk lactoperoxidase (LPO) and that sheep airway secretions contain thiocyanate (SCN(-)) at concentrations necessary and sufficient for a functional peroxidase system that can protect against infection. We also show that airway LPO, like milk LPO, produces the biocidal compound hypothiocyanite (OSCN(-)) in vitro. Finally, we show that in vivo inhibition of airway LPO in sheep leads to a significant decrease in bacterial clearance from the airways. The data suggest that the LPO system is a major contributor to airway defenses. This discovery may have significant implications for chronic airway colonization seen in respiratory diseases such as cystic fibrosis.

Iron homeostasis ensures adequate iron for biological processes while preventing excessive iron accumulation, which can lead to tissue injury. In mammalian systems, iron availability is controlled by the interaction of the iron-regulatory hormone hepcidin with ferroportin, a molecule that functions both as the hepcidin receptor as well as the sole known cellular exporter of iron. By reducing iron export through ferroportin to blood plasma, hepcidin inhibits the mobilization of iron from stores and the absorption of dietary iron. Among the many processes requiring iron, erythropoiesis is the most iron-intensive, consuming most iron circulating in blood plasma. Under conditions of enhanced erythropoiesis, more iron is required to provide developing erythroblasts with adequate iron for heme and hemoglobin synthesis. Here the hormone erythroferrone, produced by erythroblasts, acts on hepatocytes to suppress hepcidin production, and thereby increase dietary iron absorption and mobilization from stores. This review focuses on the discovery of erythroferrone and recent advances in understanding the role of this hormone in the regulation of iron homeostasis during states of increased erythropoietic demand. Gaps in our understanding of the role of erythroferrone are highlighted for future study.