Macrophages - iron homeostasis
Tissue Iron import/export

Author: monica mangioni
Date: 18/02/2008


The main function of macrophages of the reticulo-endothelial system in the iron metabolism is to recycle iron from senescent red blood cells.
Most of the iron absorbed from the diet or recycled from hemoglobin is destined for developing erythrocytes.
Every second bone marrow produces more than 2 million red blood cells. For this reason the bone marrow must regularly reach an adequate quantity of iron to produce haemoglobin.
Red blood cells live about 120 days. (Erythrocytes - iron homeostasis)
At the end of their life senescent red cells are phagocytosed by macrophages and iron released from haem by haem oxygenase 1 is returned to the circulation.
Hemoglobin is broken down by haem oxygenase 1 (HO) to liberate Fe2+ and biliverdin. The resulting water-soluble biliverdin is then converted to bilirubin by biliverdin reductase in macrophages of the reticulo-endothelial system. Bilirubin might be removed from the cell by the efflux proteins FLVCR and ABCG2.
Liberate iron passes into the labile iron pool (LIP) and is subsequently processed for efflux via IREG1 (as Fe2+). The exiting iron is re-oxidised to Fe3+ through ceruloplasmin to enable loading onto transferrin exiting iron is re-oxidised to Fe3+ through ceruloplasmin to enable loading onto transferrin. (Transferrin cycle)
Most of the iron used for blood cell production comes from this cycle of hemoglobin recycling.

Fig 1 Cellular iron transport Erythroid precursors take up iron through the transferrin cycle. Erythroid cells probably have no iron-export mechanism; essentially all iron in these cells is incorporated into haemoglobin. Reticuloendothelial macrophages carry out iron recycling. They ingest senescent red blood cells (RBC) and lyse them in a phagolysosomal compartment. Haemoglobin is degraded and iron is liberated from haem. The enzyme haem oxygenase may participate in this process. Iron is then exported through the cell. The mechanism of macrophage iron export is not known, but may again involve ferroportin1 and CP, similar to iron export from hepatocytes.

Kupffer cells

Kupffer cells are the resident macrophages of the liver.
Their main function in iron metabolism appears to be as a clearing house for iron from phagocytosed red blood cells.
Iron can be stored in Kupffer cells as ferritin. But, much of it is released back into the circulation.
Kupffer cells have been shown to strongly express both ferroportin transcript and protein. Following erythrophagocytosis the expression of many genes involved in iron metabolism, including FPN and haem oxygenase 1 , are upregulated. In these cells, FPN is localised to intracellular vesicles , redistributing to the cell surface following erythrophagocytosis. The upregulation of FPN results in an increase in iron release and its downregulation results in a decrease in iron release, consistent with involvement in iron recycling by Kupffer cells.
Kupffer cells also express TFR1, indicating that they can obtain iron from transferrin if necessary [RM Graham, 2007].

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