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

    Research output: Contribution to journalJournal articleResearchpeer-review

    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. Key Points: • Aged erythrocytes interact with the extracellular matrix of the spleen, resulting in hemolysis and ghost formation. • Ghost formation enables recognition and phagocytosis of senescent erythrocytes by RPMs.

    Original languageEnglish
    JournalBlood
    Volume136
    Issue number14
    Pages (from-to)1579-1589
    ISSN0006-4971
    DOIs
    Publication statusPublished - 1. Oct 2020

    Keywords

    • Animals
    • Biomarkers
    • Erythrocyte Aging/drug effects
    • Erythrocyte Deformability
    • Erythrocyte Membrane
    • Erythrocyte Transfusion
    • Erythrocytes/drug effects
    • Female
    • Gene Expression Profiling
    • Hemolysis
    • Histocytochemistry
    • Humans
    • Immunophenotyping
    • Laminin/pharmacology
    • Macrophages/metabolism
    • Mice
    • Phagocytosis
    • Spleen/metabolism

    Fingerprint

    Dive into the research topics of 'Hemolysis in the spleen drives erythrocyte turnover'. Together they form a unique fingerprint.

    Cite this