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Suicidal erythrocyte death in sepsis

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Abstract

Sequelae of sepsis include anemia which presumably results from accelerated clearance of erythrocytes from circulating blood. The underlying mechanisms, however, remained hitherto elusive. Most recent studies disclosed that increased cytosolic Ca2+ activity and ceramide both trigger suicidal erythrocyte death (i.e., eryptosis), which is characterized by lipid scrambling of the cell membrane leading to phosphatidylserine exposure at the erythrocyte surface. Phosphatidylserine exposing erythrocytes may adhere to vascular walls or may be engulfed by macrophages equipped with phosphatidylserine receptors. To explore whether sepsis leads to eryptosis, erythrocytes from healthy volunteers were exposed to plasma of patients suffering from sepsis, or to supernatants from sepsis producing pathogens. Then, phosphatidylserine exposure (annexin V binding), cell volume (forward scatter), cytosolic Ca2+ activity (Fluo3 fluorescence), and ceramide formation (anti-ceramide antibody) were determined by flow cytometry. Challenge of erythrocytes with plasma from the patients but not with plasma from healthy individuals triggered annexin V binding. The effect of patient plasma on erythrocyte annexin V binding was paralleled by formation of ceramide and a significant increase of cytosolic Ca2+ activity. Exposure of erythrocytes to supernatant of pathogens similarly induced eryptosis, an effect correlating with sphingomyelinase activity. The present observations disclose a novel pathophysiological mechanism leading to anemia and derangement of microcirculation during sepsis. Exposure to plasma from septic patients triggers phosphatidylserine exposure leading to adherence to the vascular wall and clearance from circulating blood.

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Acknowledgements

The authors acknowledge the meticulous preparation of the manuscript by Lejla Subasic. This study was supported by the Deutsche Forschungsgemeinschaft, Nr. La 315/6-1 and La 315/13-1, by the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (Center for Interdisciplinary Clinical Research: 01 KS 9602), the Promotionskolleg Molecular Medicine # 1547, and the Dr. Karl Kuhn-Stiftung. Daniela S. Kempe and Ahmad Akel equally contributed to the study and thus share first authorship.

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Authors and Affiliations

  1. Department of Physiology, University of Tübingen, Tübingen, Germany

    Daniela S. Kempe, Ahmad Akel, Philipp A. Lang, Tobias Hermle, Peter Dreischer, Thomas Wieder & Florian Lang

  2. Department of Medicine, University of Tübingen, Tübingen, Germany

    Björn Friedrich

  3. Department of Medical Microbiology, University of Tübingen, Tübingen, Germany

    Christiane Wolz, Ulrike Schumacher, Andreas Peschel & Gerd Döring

  4. Department of Microbial Genetics, University of Tübingen, Tübingen, Germany

    Raja Biswas, Juliana Muresanu & Friedrich Götz

  5. Institute of Molecular Biology, University of Duisburg–Essen, Duisburg–Essen, Germany

    Erich Gulbins

  6. Physiologisches Institut, der Universität Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany

    Florian Lang

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  1. Daniela S. Kempe
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  2. Ahmad Akel
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  3. Philipp A. Lang
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  9. Christiane Wolz
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  14. Thomas Wieder
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  16. Florian Lang
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Correspondence to Florian Lang.

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Kempe, D.S., Akel, A., Lang, P.A. et al. Suicidal erythrocyte death in sepsis. J Mol Med 85, 273–281 (2007). https://doi.org/10.1007/s00109-006-0123-8

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  • DOI: https://doi.org/10.1007/s00109-006-0123-8

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