Role of Eryptosis in Hemorrhagic Stroke

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  FIGURE 1. The schematic illustration of canonical eryptosis signaling. Eryptosis is mainly stimulated by increased intracellular Ca2+ and ceramide. Among oxidative stress, with Cl– removal and hyperosmotic shock, activated PGE2 stimulates NSC channels, thus resulting in Ca2+ influx. In addition, hyperosmotic shock also leads to ceramide formation. Then, increased cytosolic Ca2+ activates Gardos channels, resulting in K+ efflux, together with Cl– efflux and osmotically H2O outflow, which eventually leads to cell shrinkage. Increased cytosolic Ca2+ also leads to the translocation of phosphatidylserine (PS) from the inner leaflet of the cell membrane to the erythrocyte surface by activating the scramblase and inhibiting the flippase. In addition, increased cytosolic Ca2+ further mediates the activation of the calpain, which leads to cell membrane blebbing. Energy depletion triggers eryptosis, mainly by PKC-dependent membrane proteins phosphorylation. NSC, non-selective cation; SM, sphingomyelinase; PKC, protein kinase C; COX, cyclooxygenase; PGE2, prostaglandin E2; AA, arachidonic acid; PLA2, phospholipase A2; and PAF, platelet-activating factor.