Hemolysis in the spleen facilitates erythrocyte turnover

Red pulp macrophages of the spleen mediate daily turnover of billions of senescent erythrocytes. However, the exact molecules and mechanisms involved in sequestration of senescent erythrocytes, their recognition and ultimately their turnover remain unclear and are currently subject to debate. In this study we provide evidence that the splenic environment is of substantial importance in facilitating erythrocyte turnover through induction of haemolysis. Detailed characterization of human spleen and its red pulp macrophages lead to the identification of a population of erythrocytes devoid of haemoglobin without fully disintegrating, so-called erythrocyte ghosts. By in-vivo imaging and transfusion experiments we established that senescent erythrocytes are subject to haemolysis specifically within the spleen. We show that aged erythrocytes are captured by the extracellular matrix within the red pulp of the spleen and that their retention under low shear conditions is key in driving haemolysis. In contrast to senescent erythrocytes, the erythrocyte ghost shells were found to be prone to recognition and breakdown by red pulp macrophages. As such, these data put forward haemolysis as an efficient mechanism for the turnover of senescent erythrocytes which alters our current understanding on how erythrocyte turnover is regulated.