Regulatory effects of erythropoietin on heme biosynthesis in erythroid cells

During this project we investigated the cellular mechanisms underlying anemia of chronic disease, the network between iron, heme-biosynthesis, erythropoietin biology and immunology and finally, we studied the molecular mechanisms underlying dys-regulated duodenal iron absorption in human hemochromatosis. Using a cell culture model we could demonstrate that the erythropoietic hormone erythropoietin (Epo) directly modulates the synthesis of hemoglobin, the central component of red blood cells for oxygen transport This is achieved by a direct effect of Epo towards the molecular expression of erythroid amino-levulinate synthase, the key enzyme for heme biosynthesis. In addition Epo increases iron uptake in erythroid progenitor cells , which is a pre- requisite for heme synthesis and red blood cell formation. This new observation of an effect of Epo on heme biosynthesis is of pivotal clinical importance to better treat patients with the anemia of chronic disease (ACD), which is found in association with chronic infections, cancer or auto-immune disorders Secondly, we investigated the pathophysiological background of two frequent disorders of iron homeostasis. For ACD, the most frequent anemia in hospitalized patients, we could demonstrate that immune cell derived proteins, named cytokines, directly affect iron transport and storage by human macrophages leading to iron retention within this cells and limitation of iron availability to erythroid progenitor cells in the bone marrow, thus resulting in anemia. The relevance of these results was supported by our studies investigating anemia in association with Malaria and Auto-immune disorders (Crohn`s disease). In patients with hereditary hemochromatosis (HH), likewise the most frequent inherited disease in Europe, we studied the molecular mechanisms underlying to miss-regulation of duodenal iron absorption. Progressive iron accumulation in parenchyma organs such as liver, heart or pancreas associated with this disorder often results in liver and heart failure over time. We found that body iron sensing to duodenal enterocytes is impaired thus resulting in increased molecular expression of duodenal iron transporters and iron reducing enzymes. We are now trying to gain more insights into duodenal iron absorption and to specifically target transmembrane iron transport by pharmacological intervention strategies.