The Gardos effect drives erythrocyte senescence and leads to Lu/BCAM and CD44 adhesion molecule activation

Abstract

Senescence of erythrocytes is characterized by a series of changes that precede their removal from the circulation, including loss of red cell hydration, membrane shedding, loss of deformability, phosphatidyl serine exposure, reduced membrane sialic acid content, and adhesion molecule activation. Little is known about the mechanisms that initiate these changes nor is it known whether they are interrelated. In this study, we show that Ca2+-dependent K+ efflux (the Gardos effect) drives erythrocyte senescence. We found that increased intracellular Ca2+ activates the Gardos channel, leading to shedding of glycophorin-C (GPC)–containing vesicles. This results in a loss of erythrocyte deformability but also in a marked loss of membrane sialic acid content. We found that GPC-derived sialic acid residues suppress activity of both Lutheran/basal cell adhesion molecule (Lu/BCAM) and CD44 by the formation of a complex on the erythrocyte membrane, and Gardos channel–mediated shedding of GPC results in Lu/BCAM and CD44 activation. This phenomenon was observed as erythrocytes aged and on erythrocytes that were otherwise prone to clearance from the circulation, such as sickle erythrocytes, erythrocytes stored for transfusion, or artificially dehydrated erythrocytes. These novel findings provide a unifying concept on erythrocyte senescence in health and disease through initiation of the Gardos effect.

Ex Vivo Activation of Red Blood Cell Senescence by Plasma from Sickle-Cell Disease Patients: Correlation between Markers and Adhesion Consequences during Acute Disease Events

“…Recent works from Klei et al on Gardos and Piezo1 relative activities on RBC removal, by way of acting on RBC dehydration and deformability, have also shed new insights [15,40] on this mechanism. Rogers and Lew also recently described the Ca 2+ -dependent K+ efflux erythrocyte senescence driven by intracellular Ca2+ activating the Gardos channel.…”

PIEZO1, sensing the touch during erythropoiesis

“…The adhesion of senescent RBCs has been reproduced by the chemical activation of PIEZO1, but its effect on phosphatidylserine exposure has not been reported. Finally, if there is some evidence suggesting that PIEZO1 activation contributes to RBC senescence [30,84], whether PIEZO1 directly triggers phosphatidylserine exposure and phagocytosis of physiologically senescent RBCs has not been addressed yet.…”

Erythrocytes as Biomarkers of Virus and Bacteria in View of Metal Ion Homeostasis

“…MIF1 and DDT were found to exist in the erythrocyte, although the exact receptor has not been identified. In other tissues, a receptor for MIF1 and DDT is formed by CD74 and the hyaluronan receptor CD44 (Figure 1), which is also present on erythrocytes [13]. Intracellular as well as extracellular erythrocyte cytokines may be released by hemolysis or in proteincontaining micro-vesicles or micro-particles produced by the erythrocyte [14][15][16].…”

“…The sequence of events from dehydration to erythrocyte clearance from circulation have not been fully elucidated. In one recently proposed model, erythrocytes may respond to dehydration by shedding Glycophorin C-containing vesicles, thereby losing membrane sialic acid [13]. Less sialic acid would result in activation of the basal cell adhesion molecule (BCAM, also known as Lutheran antigen) and CD44 membrane proteins of the erythrocyte.…”