Hemolysis in the spleen drives erythrocyte turnover

T R L Klei*, J Dalimot, B Nota, M Veldthuis, F P J Mul, T Rademakers, M Hoogenboezem, S Q Nagelkerke, W F J van IJcken, E Oole, P Svendsen, S K Moestrup, F P J van Alphen, A B Meijer, T W Kuijpers, R van Zwieten, R van Bruggen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

19 Citations (Web of Science)

Abstract

Red pulp macrophages (RPMs) of the spleen mediate turnover of billions of senescent erythrocytes per day. However, the molecular mechanisms involved in sequestration of senescent erythrocytes, their recognition, and their subsequent degradation by RPMs remain unclear. In this study, we provide evidence that the splenic environment is of substantial importance in facilitating erythrocyte turnover through induction of hemolysis. Upon isolating human spleen RPMs, we noted a substantial lack of macrophages that were in the process of phagocytosing intact erythrocytes. Detailed characterization of erythrocyte and macrophage subpopulations from human spleen tissue led to the identification of erythrocytes that are devoid of hemoglobin, so-called erythrocyte ghosts. By using in vivo imaging and transfusion experiments, we further confirmed that senescent erythrocytes that are retained in the spleen are subject to hemolysis. In addition, we showed that erythrocyte adhesion molecules, which are specifically activated on aged erythrocytes, cause senescent erythrocytes to interact with extracellular matrix proteins that are exposed within the splenic architecture. Such adhesion molecule-driven retention of senescent erythrocytes under low shear conditions was found to result in steady shrinkage of the cell and ultimately resulted in hemolysis. In contrast to intact senescent erythrocytes, the remnant erythrocyte ghost shells were prone to recognition and breakdown by RPMs. These data identify hemolysis as a key event in the turnover of senescent erythrocytes, which alters our current understanding of how erythrocyte degradation is regulated.

Original languageEnglish
Pages (from-to)1579-1589
Number of pages11
JournalBlood
Volume136
Issue number14
DOIs
Publication statusPublished - 1 Oct 2020
Externally publishedYes

Keywords

  • RED-BLOOD-CELLS
  • IN-VIVO
  • ADHESION MOLECULES
  • PULP MACROPHAGES
  • CLEARANCE
  • CONSEQUENCES
  • PHAGOCYTOSIS
  • MECHANISMS
  • PHYSIOLOGY
  • RECEPTOR

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