Mechanisms and significance of eryptosis

Suicidal death of erythrocytes (eryptosis) is characterized by cell shrinkage, membrane blebbing, activation of proteases, and phosphatidylserine exposure at the outer membrane leaflet. Exposed phosphatidylserine is recognized by macrophages that engulf and degrade the affected cells. Eryptosis is triggered by erythrocyte injury after several stressors, including oxidative stress. Besides caspase activation after oxidative stress, two signaling pathways converge to trigger eryptosis: (a) formation of prostaglandin E 2 leads to activation of Ca2+-permeable cation channels, and (b) the phospholipase A(2)-mediated release of platelet-activating factor activates a sphingomyelinase, leading to formation of ceramide. Increased cytosolic Ca2+ activity and enhanced ceramide levels lead to membrane scrambling with subsequent phosphatidylserine exposure. Moreover, Ca2+ activates Ca2+-sensitive K+ channels, leading to cellular KCI loss and cell shrinkage. In addition, Ca2+ stimulates the protease calpain, resulting in degradation of the cytoskeleton. Eryptosis is inhibited by erythropoietin, which thus extends the life span of circulating erythrocytes. Eryptosis may be a mechanism of defective erythrocytes to escape hemolysis. Conversely, excessive eryptosis favors the development of anemia. Conditions with excessive eryptosis include iron deficiency, lead or mercury intoxication, sickle cell anemia, thalassemia, glucose 6- phosphate dehydrogenase deficiency, malaria, and infection with hemolysin-forming pathogens.