Reticulocyte-secreted exosomes bind natural IgM antibodies: involvement of a ROS-activatable endosomal phospholipase iPLA2

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Abstract
Reticulocytes release small membrane vesicles termed exosomes during their maturation into erythrocytes. It has been suggested that reticulocytes remodel the plasma membrane of the immature red cell during erythropoiesis by specifically eliminating various proteins. We report here that exosome release is associated with a physiologic cascade induced by the expression of a 15-lipoxygenase at the reticulocyte stage. We found that the phospholipase iPLA2 specifically associated with the endosomal and exosomal membranes could be activated by reactive oxygen species (ROSs) produced during mitochondria degeneration induced by 15-lipoxygenase. Since iPLA2 has recently been demonstrated to participate in the clearance of apoptotic cells, we investigated its role in vesicle removal. We found that exosomes isolated directly from the blood of an anemic rat or released during in vitro maturation of rat reticulocytes bind IgM antibodies on their surface, in contrast to immature and mature red cells. These natural IgM antibodies recognize lysophosphatidylcholine and are able to specifically bind to apoptotic cells. Finally, evidence of C3 deposition on the exosome surface leads us to hypothesize that this cascade may favor the clearance of exosomes by cells once released into the bloodstream, via a mechanism similar to that involved in the elimination of apoptotic cells.