Mechanisms and significance of eryptosis, the suicidal death of erythrocytes

Abstract

Eryptosis, the suicidal death of erythrocytes, is characterized by erythrocyte shrinkage, blebbing, and phospholipid scrambling of the cell membrane. Eryptosis is triggered by increased cytosolic Ca(2+) activity, which may result from Ca(2+) entry through PGE(2)-activated Ca(2+)-permeable cation channels. The Ca(2+) sensitivity of the scrambling machinery is enhanced by ceramide, which is formed by an acid sphingomyelinase, an enzyme stimulated by platelet-activating factor. Eryptosis is enhanced in a variety of clinical conditions such as sickle-cell anemia, β-thalassemia, glucose-6-phosphate dehydrogenase deficiency, hereditary spherocytosis, paroxysmal nocturnal hemoglobinuria, myelodysplastic syndrome, phosphate depletion, iron deficiency, sepsis, hemolytic uremic syndrome, renal insufficiency, diabetes, malaria, mycoplasma infection, and Wilson's disease. Eryptosis is enhanced in mouse models of sickle cell anemia and thalassemia, as well as in mice lacking functional annexin 7, cGMP-dependent protein kinase type I, AMP-activated protein kinase, Janus kinase 3, anion exchanger 1, adenomatous polyposis coli, or Klotho. Eryptosis is triggered by osmotic shock, oxidative stress, energy depletion, hyperthermia, and a myriad of small molecules. Eryptosis is inhibited by a variety of substances including nitric oxide and catecholamines. Erythropoietin counteracts eryptosis in part by inhibiting the Ca(2+)-permeable cation channels. Excessive erythropoietin concentrations lead, however, to formation of erythrocytes, which are particularly sensitive to eryptotic stimuli. Accelerated eryptosis may be compensated by enhanced erythropoiesis, which is apparent from reticulocytosis. If the compensation is not sufficient, clinically relevant anemia develops. Beyond that, adhesion of eryptotic erythrocytes to the vascular wall may lead to impairment of microcirculation.