Description:
As we approach the 20th anniversary of the first description of the central iron-regulatory hormone hepcidin and its molecular target, the cellular iron exporter ferroportin, we will take the opportunity to delve more deeply into the regulation of this axis in normal homeostasis, the cellular mediators of iron metabolism and the contribution of iron status to morbidity/mortality in diseases of ineffective hematopoiesis. Hepcidin expression and subsequent iron flux through intestinal absorption and reticuloendothelial macrophage release is regulated through iron status, erythropoietic drive, and inflammatory mediators. In addition to these systemic regulatory mechanisms, there is an emerging role of intestinal regulation of iron handling by local HIF-2α. Recent work demonstrates that hepatic hepcidin regulates intestinal HIF-2α, and this axis can be targeted in iron-related disorders.

Reticuloendothelial macrophages are the primary source of iron for erythropoiesis given their ability to recycle hemoglobin-derived iron. However, macrophages also have considerable functional and phenotypic plasticity directed by signals from the microenvironment, including iron. The spectrum of macrophage phenotypes derived from exposure to differing iron sources (e.g., hemoglobin, heme, iron) could modulate the inflammatory response, oxidative stress, and natural history of iron-loaded and hemolytic disease states. The primary toxicity of excess iron is mediated through oxidant generation and oxidative stress, which contribute to a variety of human disease states. Although this toxicity is a well-recognized contributor to organ damage/failure and mortality in iron-loading anemias, the association with poor outcomes in hematologic malignancy, and stem cell transplant is becoming established. Well-designed large trials have revealed the deleterious effects of iron overload in myelodysplastic syndrome (MDS) and the beneficial effects of iron chelation.

Dr. Yatrik Shah will describe how cell autonomous oxygen signaling pathways integrate with systemic hepcidin signaling to control intestinal iron absorption. Intestinal HIF-2α is essential for the local absorptive response to systemic iron deficiency and iron overload. Recent work has uncovered a hetero-tissue crosstalk mechanism, whereby hepatic hepcidin regulates intestinal HIF-2α in iron deficiency, anemia, and iron overload. A decrease in systemic hepcidin alters the activity on intestinal PHDs, which subsequently leads to the stabilization of HIF-2α. Pharmacological targeting of HIF-2α using a clinically relevant and highly specific inhibitor successfully treated iron overload in mouse models. These findings demonstrate a molecular link between hepatic hepcidin and intestinal HIF-2α that controls physiological iron uptake and drives iron hyperabsorption during iron overload.

Dr. Francesca Vinchi will demonstrate how the modulation of macrophage plasticity through the application of either iron sources or scavengers/chelators achieves therapeutic effects that improve disease conditions. Along with the regulation of iron homeostasis, macrophages play a crucial role in the orchestration of inflammatory and tissue remodeling processes through the acquisition of distinct functional phenotypes in response to the surrounding microenvironment. The iron-related and immune functions of macrophages are tightly interconnected: on the one hand, macrophage polarization dictates the expression of iron-regulated genes and determines cell iron handling; on the other, iron availability affects macrophage immune effector functions. Recent observations support a role for free heme and iron in shaping macrophage plasticity towards a pro-inflammatory phenotype. These findings have implications for the pathophysiology of diseases hallmarked by elevated circulating heme and iron, including hemolytic diseases and transfusion- or iv iron-dependent anemias, as well as conditions associated with increased local heme and iron accumulation, including trauma, atherosclerosis, and tumors.

Dr. Nobert Gatterman will address the impact of iron overload and chelation in patients with myelodysplastic syndrome (MDS). There is no reason to believe that transfusional iron overload (IOL) is less toxic in elderly MDS patients than young thalassemia patients. Comorbidities, in particular cardiac problems, may increase vulnerability to the toxic effects of IOL in elderly MDS patients. Nevertheless, the prognostic impact of IOL is more challenging to prove in MDS, due to considerable overlap between iron-related and age-related clinical problems. Registry studies have consistently shown a survival benefit of iron chelation therapy (ICT) in lower-risk MDS. At least two registry studies have reached high quality through extensive matched-pair-analyses, virtually eliminating the bias resulting from uneven distribution of comorbidities and performance scores. The prognostic impact of ICT has recently been corroborated by improved EFS shown in the randomized Telesto trial.