Involvement of phosphatidylserine exposure in the recognition and phagocytosis of uremic erythrocytes

Cell surface-exposed phosphatidylserine (PS) represents a signal for macrop hage recognition and cell phagocytosis. This study examines PS exposure and susceptibility to erythrocyte phagocytosis in patients with chronic uremia In an attempt to assess the possible pathogenic mechanism behind cell remo val in a condition associated with shortened erythrocyte life. Both PS-expr essing erythrocytes and erythrophagocytosis (human monocyte-derived macroph ages ingesting one or more erythrocytes) were significantly increased in ur emic patients compared with healthy controls. Phagocytosed uremic erythrocy tes appeared intact, suggesting they were identified before lysis through s ome surface change recognized by the macrophages. The degree of phagocytosi s was markedly greater for PS-positive than PS-negative fluorescence-activa ted cell sorter (FACS)-sorted uremic erythrocytes. A significant correlatio n (r = 0.655) was found between the percentage of PS-expressing red blood c ells (RBCs) and the percentage of phagocytosing macrophages in uremic patie nts. Reconstitution experiments showed the ability of uremic plasma to prom ote both PS exposure and erythrophagocytosis, the latter without direct int eraction with the macrophage population. Phagocytosis of uremic erythrocyte s was strongly inhibited when the macrophages were preincubated with glycer ophosphorylserine (GPS), a structural derivative of PS, but this was not th e case with the equivalent derivative of phosphatidylethanalamine, glycerop hosphoryiethanolamine. This inhibition appeared to be specific because GPS failed to inhibit the phagocytosis of opsonized uremic erythrocytes that oc curs through an Fc receptor-mediated pathway. These findings suggest that a PS-recognition mechanism may promote the susceptibility of uremic RBCs to phagocytosis and thus be involved in the shortened erythrocyte life span of uremia. (C) 2001 by the National Kidney Foundation, Inc.