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Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment

Nature volume 418, pages 200–203 (2002)Cite this article

Abstract

Macrophage recognition and ingestion of ‘self’ cells undergoing apoptosis in vivo protects tissues from the toxic contents of dying cells and modulates macrophage regulation of inflammatory and immune responses1,2. However, the complex molecular mechanisms mediating macrophage discrimination between viable and apoptotic cells are poorly understood2,3. In particular, little is known of why viable nucleated cells are not engulfed by macrophages. To reveal active repulsion of viable cells and to seek specific capture or ‘tethering’ of apoptotic cells, we studied macrophage binding of viable and apoptotic leukocytes under conditions of flow. We found that homophilic ligation of CD31 (ref. 4) on viable leukocytes promoted their active, temperature-dependent detachment under low shear, whereas such CD31-mediated detachment was disabled in apoptotic leukocytes, promoting tight binding and macrophage ingestion of dying cells. Here we propose that CD31 (also known as platelet-endothelial cell adhesion molecule-1, PECAM-1) is an example of a cell-surface molecule that prevents phagocyte ingestion of closely apposed viable cells by transmitting ‘detachment’ signals, and which changes function on apoptosis, promoting tethering of dying cells to phagocytes.

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Figure 1: Specific failure of viable leukocytes to attach to macrophage monolayers under flow conditions at 37 °C reflects active, temperature-dependent detachment of viable but not apoptotic leukocytes.
Figure 2: CD31 mediates tethering of proteoliposomes derived from apoptotic PMNs by macrophages.
Figure 3: Leukocyte interaction with CD31-coated coverslips under flow demonstrates that homophilic CD31 interactions mediate both attachment of apoptotic cells and detachment of viable cells.
Figure 4: Apoptosis disables CD31-mediated signalling in leukocytes.
Figure 5: CD31 on apoptotic leukocytes interacts with CD31 on phagocytes to promote engulfment.

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Acknowledgements

We would particularly like to acknowledge C. Stewart, E. Drost and W. MacNee for assisting in establishing a flow-based approach; H. Jersmann for help with a number of FACS-based phagocytosis assays; A. Rossi for help with calcium flux studies; and C. Haslett and M. Salmon for discussion. Work was funded by the Wellcome Trust, the Chief Scientist Office of the Scottish Executive, and a Wellcome Trust International Fellowship to I.H.

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Authors and Affiliations

  1. Inflammation Repair Group, MRC Centre for Inflammation Research, University of Edinburgh, EH8 9AG, Edinburgh, UK

    Simon Brown, Isabelle Heinisch, Kate Shaw & John Savill

  2. Division of Immunity & Infection, MRC Centre for Immune Regulation, University of Birmingham, Birmingham, B15 2TT, UK

    Ewan Ross & Chris D. Buckley

  3. Infection, MRC Centre for Immune Regulation, University of Birmingham,

    Ewan Ross & Chris D. Buckley

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  1. Simon Brown
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Correspondence to Simon Brown.

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Brown, S., Heinisch, I., Ross, E. et al. Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment. Nature 418, 200–203 (2002). https://doi.org/10.1038/nature00811

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