ERYFER

Erythropoiesis is the process by which the hematopoietic tissue of the bone marrow produces red blood cells (erythrocytes). The principal function of erythrocytes is to deliver oxygen from the lungs to the other tissues of the body. To perform their duty as oxygen carriers, erythrocytes require iron. Failure to incorporate adequate iron into heme results in impaired erythrocyte maturation, leading to microcytic, hypochromic anemia. The erythroblasts mature in organized niches called erythroblastic island consisting of a central macrophage that extends cytoplasmic protrusion to a ring of surrounding erythroblasts. Although the feature of erythroblast islands is now recognized as an important contributor to normal erythroid development, as well as altered erythropoiesis in diverse diseases, as anemia of inflammation and chronic disease, myelodysplasia, thalassemia, and malarial anemia, how macrophages support erythroid maturation is poorly understood. The most important systemic factors that influence iron availability is hepcidin, a circulating peptide that maintains iron homeostasis. Hepcidin is an hyposideremic hormone made predominantly by hepatocytes acting to downregulate iron absorption by the duodenal cells and iron release by the macrophages. Elevated levels of hepcidin in the bloodstream shut off iron absorption, and, conversely, low levels of circulating hepcidin allow increased iron export into the bloodstream. Aberrations in hepcidin expression or responsiveness to hepcidin result in disorders of iron deficiency and iron overload, which represent an important public health issue worldwide. As befits an iron regulatory hormone, hepcidin gene expression is highly regulated by the iron status of the body. While the molecular mechanisms of hepcidin induction by iron begin to be relatively well understood, not much is known concerning the absolute requirement of hepcidin repression in conditions of anemia, accelerated erythropoiesis and hypoxia to stimulate iron release by duodenal and macrophagic cells. Several line of evidence indicate that erythroid precursors most likely communicate directly their iron needs to the liver to influence the production of hepcidin and thus the amount of iron available for use. However, the mechanism by which erythroid cells modulate hepcidin production of liver cells has not yet been elucidated. The major goal of this application is to identify soluble molecules released by erythroid cells during their differentiation and to study their role in iron metabolism both at the central level, through the regulation of hepcidin production by liver cells, and at the local level, through their effects to the bone marrow macrophages. The ability of these molecules to regulate hepcidin production by liver cells will be tested by Partner 1 and Partner 2 will determine whether these molecules can also modify the physiology of the erythroblastic island macrophages. The question of whether the liver serine protease matriptase 2, a recently characterized hepcidin gene repressor, is the link between these soluble factors and hepcidin gene expression will be specifically addressed through ex vivo and in vivo studies through the generation and analysis of different mouse models. Improved understanding of how soluble erythroid factors impact on iron homeostasis locally, through maintaining the physiological integrity of the erythroid island, and systematically, through regulation of hepcidin synthesis, will be important to limit iron-mediated pathology, in particular anemia, a condition that affected one-quarter of the world’s population and constitutes a public health problem in both developing and industrialized countries.