Induction of eryptosis by cyclosporine

Abstract

Side effects of cyclosporine treatment include anemia. Most recent studies have found that anemia may be caused by triggering of suicidal erythrocyte death (eryptosis), i.e. activation of an erythrocyte scramblase and phosphatidylserine exposure at the erythrocyte surface. Phosphatidylserine exposing cells are rapidly cleared from circulating blood by phagocytosis. Stimulators of erythrocyte membrane scrambling include cytosolic Ca(2+) and ceramide, which are increased by entry through Ca2+-permeable cation channels and by activation of a sphingomyelinase, respectively. The present study has been performed to test for an effect of cyclosporine on eryptosis. Erythrocytes from healthy volunteers were exposed to cyclosporine, and phosphatidylserine exposure (annexin V binding), cell volume (forward scatter), cytosolic Ca2+ activity (Fluo3-dependent fluorescence), ceramide formation (anti-ceramide-FITC antibody), and 45Ca2+ uptake were determined by flow cytometry and tracer flux measurements, respectively. Exposure of erythrocytes to cyclosporine triggered annexin V binding and significantly enhanced the increased annexin V binding both following glucose depletion and after hyperosmotic or isotonic cell shrinkage. However, cyclosporine significantly decreased cytosolic Ca2+ activity and did not stimulate 45Ca2+ uptake. Instead, cyclosporine transiently stimulated ceramide formation, decreased the cytosolic ATP concentration and potentiated the decline of cytosolic ATP concentration following glucose depletion. Elevated ceramide levels and ATP depletion, in turn, sensitize the erythrocytes for the eryptotic effects of Ca2+. The present observations may provide a mechanistic explanation for the anemia following treatment with this important immunosuppressive drug.

Hemin-induced suicidal erythrocyte death

“…Some of these diseases may cause eryptosis by stimulating the formation of hemin. Furthermore, several eryptosis-triggering xenobiotics and endogeneous substances have been identified, such as cordycepin [50], methylglyoxal [54], amyloid peptides [53], lipopetides [71] retinoic acid [55], paclitaxel [44], amantadine [23], chlorpromazine [1], ciglitazone [58], cyclosporine [56], Bay-5884 [65], curcumin [4], valinomycin [64], listeriolysin [25], aluminum [57], copper [46], bismuth [13], tin [52], cadmium [68], selenium [67], vanadate [27], gold [69], and arsenic [51]. At least in theory, some of those substances may be effective through stimulation of hemin formation.…”

Erythrocyte programmed cell death

“…Suicidal erythrocyte death could be triggered by ligation of specific surface antigens, such as glycophorin-C (41), the thrombospondin-1 receptor CD47 (42) and the death receptor CD95/Fas (43). Further stimulators of eryptosis include ceramide (acylsphingosine) (44), prostaglandin E 2 (45), platelet activating factor (46), anti A IgG antibodies (47), hemolysin from Vibrio parahaemolyticus (48), listeriolysin (49), paclitaxel (50), amantadine (51), azathioprine (52), retinoic acid (53), chlorpromazine (54), cyclosporine (55), methylglyoxal (56), amyloid peptides (57), anandamide (58), Bay-Y5884 (59), curcumin (60), valinomycin (61), aluminium (62), mercury (63), lead (64), gold (65), vanadium (66) and copper (67).…”

“…Eryptosis could be triggered by increase in the cytosolic Ca 21 activity, which leads to cell membrane vesiculation (68) and stimulates cell membrane scrambling resulting in phosphatidylserine exposure at the cell surface (54)(55)(56). Ca 21 further stimulates the cysteine endopeptidase calpain, which degrades the cytoskeleton and thus facilitates cell membrane blebbing (69) (Fig.…”

Lipopeptides in the Triggering of Erythrocyte Cell Membrane Scrambling

“…Phosphatidylserine exposure in erythrocytes could further be elicited by ligation of specific surface antigens, such as glycophorin-C [14], of CD47, 382 the critical RBC antigenic marker that exhibits an inhibitory role in macrophage activation [15], and of the death receptor CD95/Fas [16]. Moreover, eryptosis is triggered by paclitaxel [17], amantadine [18], azathioprine [19], retinoic acid [20], chlorpromazine [21], cyclosporine [22], methylglyoxal [23], amyloid peptides [24], anandamide [25], Bay-Y5884 [26] and curcumin [27]. Mechanisms underlying eryptosis may not only affect circulating erythrocytes but may contribute to the limitation of erythrocytes during storage [28][29][30].…”