Abstract
Red-blood-cells (RBCs) undergo structural and metabolic changes with prolonged storage, which ultimately may decrease their survival after transfusion. Although the storage-induced damage to RBCs has been rather well described biochemically, little is known about the mechanisms underlying the recognition and rapid clearance of the damaged cells by macrophages. We, here, used a murine model for cold (+4°C) RBC storage and transfusion. Phagocytosis of human or murine RBCs, liquid stored for 6-8weeks or 10-14days, respectively, was investigated in murine peritoneal macrophages. The effects of storage on murine RBCs resembled that described for stored human RBCs with regard to decreased adenosine triphosphate (ATP) levels, accumulation of microparticles (MPs) during storage, and RBC recovery kinetics after transfusion. Under serum-free conditions, phagocytosis of stored human or murine RBCs in vitro was reduced by 70-75%, as compared with that in the presence of heat-inactivated fetal calf serum (FCS). Human serum promoted phagocytosis of stored human RBCs similar to that seen with FCS. By adding fucoidan or dextran sulphate (blockers of scavenger receptors class A (SR-A)), phagocytosis of human or murine RBCs was reduced by more than 90%. Phagocytosis of stored human RBCs was also sensitive to inhibition by the phosphatidylinositol 3 kinase-inhibitor LY294002, the ERK1/2-inhibitor PD98059, or the p38 MAPK-inhibitor SB203580. RBCs damaged during liquid storage may be recognized by macrophage SR-A and serum-dependent mechanisms. This species-independent recognition mechanism may help to further understand the rapid clearance of stored RBCs shortly after transfusion.
Highlights
We did find that the clearance of fresh and stored murine RBCs was virtually similar when comparing the relative clearance-rate of RBCs that remained in circulation at 24 h after transfusion (Fig. 1g)
Under serum-free conditions, we found that phagocytosis of stored human or murine RBCs was reduced by 70–75%, as compared with that in the presence of heat-inactivated FCS (Fig. 2a,b)
We have previously shown that both Fcc receptor-mediated uptake of IgG-opsonized RBCs and scavenger receptor-mediated uptake of oxidized RBCs were sensitive to inhibition of phosphatidylinositol 3 (PI3) kinase, p38MAPK or ERK1/2 [13]
Summary
Transfusion of RBCs is a common practice in modern medical care, with roughly 90 million transfused units. No clear evidence has been presented for such a response in humans, except for a report in preterm infants [8]. The mechanism behind this swift macrophage-mediated phagocytosis is not well understood, but is likely due to a combination of storage-related metabolic and structural changes within the RBC population. The storage-induced damage to RBCs has been rather well described biochemically, little is known about the mechanisms underlying the recognition and rapid clearance of the damaged cells by macrophages
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