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Human CD14 mediates recognition and phagocytosis of apoptotic cells

Nature volume 392, pages 505–509 (1998)Cite this article

Abstract

Cells undergoing programmed cell death (apoptosis) are cleared rapidly in vivo by phagocytes without inducing inflammation1. Here we show that the glycosylphosphatidylinositol-linked plasma-membrane glycoprotein CD14 (refs 2, 3) on the surface of human macrophages is important for the recognition and clearance of apoptotic cells. CD14 can also act as a receptor that binds bacterial lipopolysaccharide (LPS), triggering inflammatory responses4. Overstimulation of CD14 by LPS can cause the often fatal toxic-shock syndrome5,6. Here we show that apoptotic cells interact with CD14, triggering phagocytosis of the apoptotic cells. This interaction depends on a region of CD14 that is identical to, or at least closely associated with, a region known to bind LPS. However, apoptotic cells, unlike LPS, do not provoke the release of pro-inflammatory cytokines from macrophages. These results indicate that clearance of apoptotic cells is mediated by a receptor whose interactions with ‘non-self’ components (LPS) and ‘self’ components (apoptotic cells) produce distinct macrophage responses.

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Figure 1: CD14 carries the epitope defined by monoclonal antibody 61D3.
Figure 2: CD14-mediated recognition and phagocytosis of apoptotic cells by macrophages.
Figure 3: Role of CD14 in recognition and phagocytosis of apoptotic cells.
Figure 4: Epitope mapping of the 61D3 monoclonal antibody by ELISA, using immobilized soluble recombinant CD14-Fc fusion protein.
Figure 5: Production of TNF-α by macrophages stimulated with LPS but not apoptotic cells.

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References

  1. Savill, J., Fadok, V., Henson, P. & Haslett, C. Phagocyte recognition of cells undergoing apoptosis. Immunol. Today 14, 131–136 (1993).

    Article  CAS  Google Scholar 

  2. Goyert, S. M. et al. The CD14 monocyte differentiation antigen maps to a region encoding growth factors and receptors. Science 239, 497–500 (1988).

    Article  ADS  CAS  Google Scholar 

  3. Simmons, D. L., Tan, S., Tenen, D. G., Nicholson-Weller, A. & Seed, B. Monocyte antigen CD14 is a phospholipid anchored membrane protein. Blood 73, 284–289 (1989).

    CAS  PubMed  Google Scholar 

  4. Ulevitch, R. J. & Tobias, P. S. Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu. Rev. Immunol. 13, 437–457 (1995).

    Article  CAS  Google Scholar 

  5. Ferrero, E. et al. Transgenic mice expressing human CD14 are hypersensitive to lipopolysaccharide. Proc. Natl Acad. Sci. USA 90, 2380–2384 (1993).

    Article  ADS  CAS  Google Scholar 

  6. Haziot, A. et al. Resistance to endotoxin-shock and reduced dissemination of Gram-negative bacteria in CD14-deficient mice. Immunity 4, 407–414 (1996).

    Article  CAS  Google Scholar 

  7. Flora, P. K. & Gregory, C. D. Recognition of apoptotic cells by human macrophages-inhibition by a monocyte/macrophage-specific monoclonal antibody. Eur. J. Immunol. 24, 2625–2632 (1994).

    Article  CAS  Google Scholar 

  8. Juan, T. S. C. et al. Identification of a lipopolysaccharide binding domain in CD14 between amino acids 57 and 64. J. Biol. Chem. 270, 5219–5224 (1995).

    Article  CAS  Google Scholar 

  9. Savill, J., Dransfield, I., Hogg, N. & Haslett, C. Vitronectin receptor-mediated phagocytosis of cells undergoing apoptosis. Nature 343, 170–173 (1990).

    Article  ADS  CAS  Google Scholar 

  10. Savill, J., Hogg, N., Ren, Y. & Haslett, C. Thrombospondin cooperates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. J. Clin. Invest. 90, 1513–1522 (1992).

    Article  CAS  Google Scholar 

  11. Platt, N., Suzuki, H., Kurihara, Y., Kodama, T. & Gordon, S. Role for the class A macrophage scavenger receptor in the phagocytosis of apoptotic thymocytes in vitro. Proc. Natl Acad. Sci. USA 93, 12456–12460 (1996).

    Article  ADS  CAS  Google Scholar 

  12. Luciani, M.-F. & Chimini, G. The ATP binding cassette transporter ABC1, is required for the engulfment of corpses generated by apoptotic cell death. EMBO J. 15, 226–235 (1996).

    Article  CAS  Google Scholar 

  13. Ogasawara, J. et al. Lethal effect of the anti-Fas antibody in mice. Nature 364, 806–809 (1993).

    Article  ADS  CAS  Google Scholar 

  14. Weidemann, B. et al. Specific binding of soluble peptidoglycan and muramyldipeptide to CD14 on human monocytes. Infect. Immun. 65, 858–864 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Espevik, T. et al. The involvement of CD14 in stimulation of cytokine production by uronic acid polymers. Eur. J. Immunol. 23, 255–261 (1993).

    Article  CAS  Google Scholar 

  16. Soell, M. et al. Activation of human monocytes by streptococcal rhamnose glucose polymers is mediated by CD14 antigen, and mannan-binding protein inhibits TNF-alpha release. J. Immunol. 154, 851–860 (1995).

    CAS  PubMed  Google Scholar 

  17. Pugin, J. et al. CD14 is a pattern recognition receptor. Immunity 1, 509–516 (1994).

    Article  CAS  Google Scholar 

  18. Newman, S. L., Chaturvedi, S. & Klein, B. S. The WI-1 antigen of Blastomyces dermatitidis yeasts mediates binding to human macrophage CD11b/CD18 (CR3) and CD14. J. Immunol. 154, 753–761 (1995).

    CAS  PubMed  Google Scholar 

  19. Wright, S. D., Ramos, R. A., Tobias, P. S., Ulevitch, R. J. & Mathison, J. C. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249, 1431–1433 (1990).

    Article  ADS  CAS  Google Scholar 

  20. Duvall, E., Wyllie, A. H. & Morris, R. G. Macrophage recognition of cells undergoing programmed cell death (apoptosis). Immunology 56, 351–358 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Dini, L., Autuori, F., Lentini, A., Oliverio, S. & Piacentini, M. The clearance of apoptotic cells in the liver is mediated by the asialoglycoprotein receptor. FEBS Lett. 296, 174–178 (1992).

    Article  CAS  Google Scholar 

  22. Fadok, V. A. et al. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J. Immunol. 148, 2207–2216 (1992).

    CAS  PubMed  Google Scholar 

  23. Pradhan, D., Krahling, S., Williamson, P. & Schlegal, R. A. Multiple systems for recognition of apoptotic lymphocytes by macrophages. Mol. Biol. Cell 8, 767–778 (1997).

    Article  CAS  Google Scholar 

  24. Yu, B., Hailman, E. & Wright, S. D. Lipopolysaccharide binding protein and soluble CD14 catalyze exchange of phospholipids. J. Clin. Invest. 99, 315–324 (1997).

    Article  CAS  Google Scholar 

  25. Delude, R. L. et al. CD14 enhances cellular responses to endotoxin without imparting ligand-specific recognition. Proc. Natl Acad. Sci. USA 92, 9288–9292 (1995).

    Article  ADS  CAS  Google Scholar 

  26. Cavaillon, J. M. et al. CD14/LPS receptor exhibits lectin-like properties. J. Endotox. Res. 3, 471–480 (1996).

    Article  CAS  Google Scholar 

  27. Voll, R. E. et al. Immunosuppressive effects of apoptotic cells. Nature 390, 350–351 (1997).

    Article  ADS  CAS  Google Scholar 

  28. Fadok, V. A. et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2 and PAF. J.Clin. Invest. 101, 890–898 (1998).

    Article  CAS  Google Scholar 

  29. Petty, H. R. & Todd, R. F. Integrins as promiscuous signal transduction devices. Immunol. Today 17, 209–212 (1996).

    Article  CAS  Google Scholar 

  30. Ugolini, V., Nunez, G., Smith, R. G., Stastny, P. & Capra, J. D. Initial characterization of monoclonal antibodies against human monocytes. Proc. Natl Acad. Sci. USA 77, 6764–6768 (1980).

    Article  ADS  CAS  Google Scholar 

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Acknowledgements

This work was supported by the MRC.

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Authors and Affiliations

  1. Department of Immunology, University of Birmingham Medical School, B15 2TT, Birmingham, UK

    Andrew Devitt, Odette D. Moffatt, Chandra Raykundalia & Christopher D. Gregory

  2. Institute of Cell Signalling and School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, NG7 2UH, Nottingham, UK

    Andrew Devitt, Odette D. Moffatt & Christopher D. Gregory

  3. Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, 73104, Oklahoma, USA

    J. Donald Capra

  4. SmithKline Beecham Pharmaceuticals, New Frontiers Science Park North, Harlow, CM19 5AW, Essex, UK

    David L. Simmons

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Correspondence to Christopher D. Gregory.

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Devitt, A., Moffatt, O., Raykundalia, C. et al. Human CD14 mediates recognition and phagocytosis of apoptotic cells. Nature 392, 505–509 (1998). https://doi.org/10.1038/33169

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