Macrophages function as a ferritin iron source for cultured human erythroid precursors.
Iron is essential for the survival as well as the proliferation and maturation of developing erythroid precursors (EP) into hemoglobin-containing red blood cells. The transferrin-transferrin receptor pathway is the main route for erythroid iron uptake. Using a two-phase culture system, we have previously shown that placental ferritin as well as macrophages derived from peripheral blood monocytes could partially replace transferrin and support EP growth in a transferrin-free medium. We now demonstrate that in the absence of transferrin, ferritin synthesized and secreted by macrophages can serve as an iron source for EP. Macrophages trigger an increase in both the cytosolic and the mitochondrial labile iron pools, in heme and in hemoglobin synthesis, along with a decrease in surface transferrin receptors. Inhibiting macrophage exocytosis, binding extracellular ferritin with specific antibodies, inhibiting EP receptor-mediated endocytosis or acidification of EP lysosomes, all resulted in a decreased EP growth when co-cultured with macrophages under transferrin-free conditions. The results suggest that iron taken up by macrophages is incorporated mainly into their ferritin, which is subsequently secreted by exocytosis. Nearby EP are able to take up this ferritin probably through clathrin-dependent, receptor-mediated endocytosis into endosomes, which following acidification and proteolysis release the iron from the ferritin, making it available for regulatory and synthetic purposes. Thus, macrophages support EP development under transferrin-free conditions by delivering essential iron in the form of metabolizable ferritin.
Leimberg
Moshe J
MJ
Department of Human Nutrition and Metabolism, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
Prus
Eugenia
E
Konijn
Abraham M
AM
Fibach
Eitan
E
D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism; D018920:Coculture Techniques; D004705:Endocytosis; D011992:Endosomes / Q000502:physiology; D015672:Erythroid Precursor Cells / Q000166:cytology* / Q000502:physiology; D005089:Exocytosis; D005293:Ferritins / Q000378:metabolism*; D006418:Heme / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008247:Lysosomes / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*
D002966:Clathrin; D006418:Heme; D005293:Ferritins; D007501:Iron