Erythropoietin Withdrawal Leads to the Destruction of Young Red Cells at the Endothelial-Macrophage Interface

J.      Trial; L.      Rice

doi:10.2174/1381612043453423

Abstract

Erythropoietin is a growth factor for endothelial cells as well as for erythroid cells. In contrast to their proliferative response to physiological levels of erythropoietin, endothelial cells may respond to decreased levels by triggering a process called neocytolysis. Neocytolysis is the selective destruction of the youngest circulating red cells, which may be prompted by endothelial cells communicating with macrophages to stimulate phagocytosis of this unusual cell subset. We speculate that this is due to decreased production by endothelial cells of the macrophage-deactivating transforming growth factor-ß. The resulting proinflammatory phenotype may include macrophage production of thrombospondin, which forms bridges between adhesion molecules selectively expressed on young red cells (CD36) and the CD36 / αvß3 complex on macrophages that triggers phagocytosis. Alternatively, inflammatory mediators secreted by endothelial cells and macrophages during erythropoietin withdrawal may signal young red cells to expose phosphatidylserine, which would mark them for elimination via the normal pathway for aged red cell destruction. Neocytolysis has been demonstrated in returning astronauts and in polycythemic individuals at high altitude on descent to sea level. It contributes to the anemia of renal disease, is triggered by the rapidly falling levels of erythropoietin seen after intravenous administration, and may be the normal mechanism for reduction of red cell mass in newborns. It may play a role in chronic diseases including malaria and sickle cell anemia. New erythropoietin products and methods of administration avoid the intermittent rapid decreases associated with the stimulus for neocytolysis, but study of this phenomenon may yield further improvements in drug design.

Keywords: erythropoietin, neocytolysis, endothelial cell, macrophage, red cell, phagocytosis, anemia, inflammation, renal disease