Cellular mechanisms of erythrodieresis

Abstract

Normally erythrodieresis is in a dynamic equilibrium with the process of erythropoiesis, and is therefore one of the factors to providing a relatively constant number of red blood cells in the bloodstream. The physiologically old, damaged and non-viable erythrocytes, as well as the erythrocytes which are produced during stress erythropoiesis, are destroyed. Erythrocyte clearance is a selective process. First of all, the cells that have lost their ability to deform are removed from the bloodstream. The deformability of red blood cells depends on the shape of the cells, the viscosity of the cytoplasm and the mechanical properties of the membrane. Old and altered erythrocytes are quite rigid, and are therefore delayed in the narrow capillaries and venous sinuses of the liver and spleen. In addition, macrophages of the liver and spleen phagocytize erythrocytes, which expose “eat me” signaling molecules on their surface. Exposure of phosphatidylserine on the outer cell surface of erythrocytes and vesicles results in their elimination from the bloodstream by Kupffer cells and other mononuclear phagocytes. During the initiation of erythrophagocytosis, the phosphatidylserine of the outer lipid layer of the erythrocyte plasma membrane directly interacts with the receptors Stabilin-2, TIM-1, TIM-4 or CD300 of macrophages. The macrophage’s integrins avb3 and avb5, as well as the Mer receptor tyrosine kinase indirectly interact with the cell surface-exposed phosphatidylserine through the soluble proteins MFG-E8, Gas 6 and protein S. Clustering of the erythrocyte membrane protein band 3 cau­ses the binding of natural antibodies, and opsonization of erythrocytes with C3b enhances this process and facilitates the recognition of such cells by red pulp macrophages in the spleen. In senescent erythrocytes, the formation of the CD47-SIRPα complex («do not eat me» signal), is suppressed, and this is an additional stimulus for erythrocytes removing by splenic and liver macrophages. The purpose of the review is to describe the mechanisms of erythrophagocytosis and the molecular determinants of erythrocyte senescence and death, including eryptosis and neocytolysis, and to illustrate the substantiated facts and contradictions that exist at the present time of the study of this scientific problem.