Abstract
Human erythrocytes are organelle-free cells packaged with iron-containing hemoglobin, specializing in the transport of oxygen. With a total number of approximately 25 trillion cells per individual, the erythrocyte is the most abundant cell type not only in blood but in the whole organism. Despite their low complexity and their inability to transcriptionally upregulate antioxidant defense mechanisms, they display a relatively long life time, of 120 days. This ensures the maintenance of tissue homeostasis where the clearance of old or damaged erythrocytes is kept in balance with erythropoiesis. Whereas the regulatory mechanisms of erythropoiesis have been elucidated over decades of intensive research, the understanding of the mechanisms of erythrocyte clearance still requires some refinement. Here, we present the main pathways leading to eryptosis, the programmed death of erythrocytes, with special emphasis on Ca2+ influx, the generation of ceramide, oxidative stress, kinase activation, and iron metabolism. We also compare stress-induced erythrocyte death with erythrocyte ageing and clearance, and discuss the similarities between eryptosis and ferroptosis, the iron-dependent regulated death of nucleated blood cells. Finally, we focus on the pathologic consequences of deranged eryptosis, and discuss eryptosis in the context of different infectious diseases, e.g., viral or parasitic infections, and hematologic disorders.
Highlights
Erythrocytes are organelle-free cells possessing huge amounts of iron-containing tetrameric hemoglobin (Hb)
Their study showed that (i) ceramides are formed following sphingomyelin breakdown after challenge of erythrocytes with hyperosmotic solutions, (ii) hyperosmotic shock-induced eryptosis is blunted by inhibitors of sphingomyelinase, and (iii) the proeryptotic effects of hyperosmotic shock can be mimicked by cell-membrane-permeable ceramides or by the addition of sphingomyelinase [32]
Further studies revealed that erythropoietin protects erythrocytes against oxidative stress [54,55], and the hormone may be useful for the treatment of patients suffering from decompensated autoimmune hemolytic anemia [56]
Summary
Erythrocytes are organelle-free cells possessing huge amounts of iron-containing tetrameric hemoglobin (Hb). Pathways of Programmed Erythrocyte Death About one percent of the human erythrocyte pool of 25 × 1012 cells per individual, which means approximately 250 × 109 cells, must be removed from the circulation every day As erythrocytes lose their organelles during the differentiation process, they are unable to proliferate and can be considered senescent. In 2003, it was shown by patch clamp technique that hyperosmotic shock and oxidative stress, two well-known triggers of programmed cell death in nucleated cells, activate Ca2+-permeable cation channels, thereby increasing the intracellular Ca2+ concentration [15]. It was shown that ionomycin-mediated increases in intracellular Ca2+ activate inwardly rectifying K+-selective channels in the erythrocyte membrane, leading to a significant decrease in cell volume. Future studies on cell volume and channel regulation by gaseous substances such as NO [26] or H2S [27] will lead to new insights into the molecular mechanisms leading to the accelerated death of this cell type
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