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Engulfment of apoptotic cells involves the redistribution of membrane phosphatidylserine on phagocyte and prey

Nature Cell Biology volume 1, pages 454–456 (1999)Cite this article

The clearance of cells that are dying by apoptosis is essential to the control of tissue homeostasis1. In contrast to classical models of phagocytosis, the molecular dissection of engulfment of apoptotic cells is still preliminary1. Genetic approaches in Caenorhabditis elegans have yielded several mutants, characterized by the persistence of apoptotic corpses2,3,4,5. In mammals, in vitro studies have mostly shed light on the macrophage receptors engaged in the recognition of apoptotic surfaces1,6. Both of these approaches highlighted the importance of an ATP-binding cassette (ABC)-type transporter, named CED-7 in C. elegans and ABC1 in mouse4,7. The requirement for ABC1 on the macrophage surface is specific to the engulfment7. Here we assess the distinctive features of engulfment in comparison with other forms of phagocytosis, and find that engulfment exhibits a unique sensitivity to the ABC1 blocker glyburide8. In addition, glyburide, as well as antimycin and oligomycin, affects membrane behaviour in both partners of engulfment: when applied to either phagocyte or prey, these drugs impair the Ca2+-induced transmembrane randomization of phospholipids9. Our results show that engulfment requires a symmetrical transbilayer movement of lipids across the membranes of both the phagocyte and the prey.

However, sensitivity to glyburide8 was correlated to the particle to be ingested (Fig. 1B). The uptake of yeast or opsonized sheep red blood cells was unaffected by the drug (yeast, 97 ± 8% of control; opsonized cells, 98.8 ± 3% of control) whereas the engulfment of apoptotic thymocytes was reduced to 56 ± 8% of control. As the larger size of the apoptotic thymocytes could influence the mechanics of engulfment, we checked that the ingestion of opsonized apoptotic thymocytes was insensitive to glyburide (116 ± 11% of control). Finally, we showed that the engulfment of fixed and unfixed apoptotic cells was equally efficient and sensitive to glyburide (fixed, 66 ± 3% of control; unfixed, 56 ± 8% of control), thus ruling out the possibility that glyburide acts by blocking the ABC1-mediated transport of a substrate released from the cell.

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Figure 1: Engulfment-specific drugs affect both the phagocyte and the prey.
Figure 2: Glyburide and oligomycin affect Ca2+-induced lipid randomization on mouse thymocytes and macrophages.

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Acknowledgements

We thank J.F. Brunet and P. Golstein for discussions; J.-M. Freyssinet for providing recombinant annexin-V; and H. Zheng for providing IL-1-deficient mice. This work was supported by institutional grants from INSERM and CNRS, by a specific CNRS grant on cell biology (number 96039/2), and by ARC.

Correspondence and requests for materials should be addressed to G.C.

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Authors and Affiliations

  1. Centre d’Immunologie INSERM-CNRS de Marseille-Luminy, Case 906, Marseille, 13288 Cedex 09, France

    Didier Marguet, Marie-Francoise Luciani, Alix Moynault & Giovanna Chimini

  2. Department of Biology, Amherst College, Amherst, 01002, Massachussetts, USA

    Patrick Williamson

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  1. Didier Marguet
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Correspondence to Giovanna Chimini.

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Marguet, D., Luciani, MF., Moynault, A. et al. Engulfment of apoptotic cells involves the redistribution of membrane phosphatidylserine on phagocyte and prey. Nat Cell Biol 1, 454–456 (1999). https://doi.org/10.1038/15690

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