Skip to main content
PMC home page
Molecular Biology of the Cell logoLink to Molecular Biology of the Cell
. 1997 May;8(5):767–778. doi: 10.1091/mbc.8.5.767

Multiple systems for recognition of apoptotic lymphocytes by macrophages.

D Pradhan 1, S Krahling 1, P Williamson 1, R A Schlegel 1
PMCID: PMC276128  PMID: 9168465

Abstract

In vivo, apoptotic lymphocytes are recognized and phagocytosed by macrophages well before the final stages of DNA degradation and cell lysis. The recognition process is apparently triggered by the exposure of phosphatidylserine (PS) on the cell surface, an event which precedes cell lysis by several hours. However, multiple receptors appear to respond to this event. We demonstrate here that both activated and unactivated macrophages recognize PS, but with different receptor systems. Phagocytosis of apoptotic lymphocytes by activated (but not by unactivated) macrophages is inhibited by pure PS vesicles as well as by N-acetylglucosamine, implicating involvement of a lectin-like receptor in this case. Conversely, uptake of apoptotic lymphocytes by unactivated (but not by activated) macrophages is inhibited by PS on the surface of erythrocytes as well as by the tetrapeptide RGDS and cationic amino acids and sugars, implicating involvement of the vitronectin receptor in this case. Recognition by both classes of macrophages is blocked by the monocyte-specific monoclonal antibody 61D3. The signal recognized by activated macrophages appears to develop on the lymphocyte prior to assembly of the signal recognized by unactivated macrophages. Collectively, these results suggest that PS exposure on the surface of apoptotic lymphocytes generates a complex and evolving signal recognized by different receptor complexes on activated and unactivated macrophages.

Full text

PDF
767

Images in this article

770Image
on p.770
771Image
on p.771
772Image
on p.772
772Image
on p.772
773Image
on p.773
773Image
on p.773
774Image
on p.774
775Image
on p.775

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Acton S., Rigotti A., Landschulz K. T., Xu S., Hobbs H. H., Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science. 1996 Jan 26;271(5248):518–520. doi: 10.1126/science.271.5248.518. [DOI] [PubMed] [Google Scholar]
  2. Akbar A. N., Savill J., Gombert W., Bofill M., Borthwick N. J., Whitelaw F., Grundy J., Janossy G., Salmon M. The specific recognition by macrophages of CD8+,CD45RO+ T cells undergoing apoptosis: a mechanism for T cell clearance during resolution of viral infections. J Exp Med. 1994 Nov 1;180(5):1943–1947. doi: 10.1084/jem.180.5.1943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Allen T. M., Austin G. A., Chonn A., Lin L., Lee K. C. Uptake of liposomes by cultured mouse bone marrow macrophages: influence of liposome composition and size. Biochim Biophys Acta. 1991 Jan 9;1061(1):56–64. doi: 10.1016/0005-2736(91)90268-d. [DOI] [PubMed] [Google Scholar]
  4. Cohen J. J., Duke R. C., Fadok V. A., Sellins K. S. Apoptosis and programmed cell death in immunity. Annu Rev Immunol. 1992;10:267–293. doi: 10.1146/annurev.iy.10.040192.001411. [DOI] [PubMed] [Google Scholar]
  5. Duvall E., Wyllie A. H., Morris R. G. Macrophage recognition of cells undergoing programmed cell death (apoptosis). Immunology. 1985 Oct;56(2):351–358. [PMC free article] [PubMed] [Google Scholar]
  6. Fadok V. A., Laszlo D. J., Noble P. W., Weinstein L., Riches D. W., Henson P. M. Particle digestibility is required for induction of the phosphatidylserine recognition mechanism used by murine macrophages to phagocytose apoptotic cells. J Immunol. 1993 Oct 15;151(8):4274–4285. [PubMed] [Google Scholar]
  7. Fadok V. A., Savill J. S., Haslett C., Bratton D. L., Doherty D. E., Campbell P. A., Henson P. M. Different populations of macrophages use either the vitronectin receptor or the phosphatidylserine receptor to recognize and remove apoptotic cells. J Immunol. 1992 Dec 15;149(12):4029–4035. [PubMed] [Google Scholar]
  8. Fadok V. A., Voelker D. R., Campbell P. A., Cohen J. J., Bratton D. L., Henson P. M. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol. 1992 Apr 1;148(7):2207–2216. [PubMed] [Google Scholar]
  9. Flora P. K., Gregory C. D. Recognition of apoptotic cells by human macrophages: inhibition by a monocyte/macrophage-specific monoclonal antibody. Eur J Immunol. 1994 Nov;24(11):2625–2632. doi: 10.1002/eji.1830241109. [DOI] [PubMed] [Google Scholar]
  10. Koopman G., Reutelingsperger C. P., Kuijten G. A., Keehnen R. M., Pals S. T., van Oers M. H. Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood. 1994 Sep 1;84(5):1415–1420. [PubMed] [Google Scholar]
  11. Krieger M., Herz J. Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). Annu Rev Biochem. 1994;63:601–637. doi: 10.1146/annurev.bi.63.070194.003125. [DOI] [PubMed] [Google Scholar]
  12. Lee K. D., Nir S., Papahadjopoulos D. Quantitative analysis of liposome-cell interactions in vitro: rate constants of binding and endocytosis with suspension and adherent J774 cells and human monocytes. Biochemistry. 1993 Jan 26;32(3):889–899. doi: 10.1021/bi00054a021. [DOI] [PubMed] [Google Scholar]
  13. Martin S. J., Reutelingsperger C. P., McGahon A. J., Rader J. A., van Schie R. C., LaFace D. M., Green D. R. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J Exp Med. 1995 Nov 1;182(5):1545–1556. doi: 10.1084/jem.182.5.1545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. McEvoy L., Williamson P., Schlegel R. A. Membrane phospholipid asymmetry as a determinant of erythrocyte recognition by macrophages. Proc Natl Acad Sci U S A. 1986 May;83(10):3311–3315. doi: 10.1073/pnas.83.10.3311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Morris R. G., Hargreaves A. D., Duvall E., Wyllie A. H. Hormone-induced cell death. 2. Surface changes in thymocytes undergoing apoptosis. Am J Pathol. 1984 Jun;115(3):426–436. [PMC free article] [PubMed] [Google Scholar]
  16. Nunez G., Ugolini V., Capra J. D., Stastny P. Monoclonal antibodies against human monocytes. II. Recognition of two distinct cell surface molecules. Scand J Immunol. 1982 Dec;16(6):515–523. doi: 10.1111/j.1365-3083.1982.tb00753.x. [DOI] [PubMed] [Google Scholar]
  17. Ottnad E., Parthasarathy S., Sambrano G. R., Ramprasad M. P., Quehenberger O., Kondratenko N., Green S., Steinberg D. A macrophage receptor for oxidized low density lipoprotein distinct from the receptor for acetyl low density lipoprotein: partial purification and role in recognition of oxidatively damaged cells. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1391–1395. doi: 10.1073/pnas.92.5.1391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Pinson D. M., Phillips T. A., Pace J. L., MacKay R. J., Russell S. W. Activation-associated marker proteins: peptide mapping and their expression in macrophage cell lines. Biochem Biophys Res Commun. 1991 Apr 30;176(2):882–886. doi: 10.1016/s0006-291x(05)80268-2. [DOI] [PubMed] [Google Scholar]
  19. Pradhan D., Williamson P., Schlegel R. A. Phosphatidylserine vesicles inhibit phagocytosis of erythrocytes with a symmetric transbilayer distribution of phospholipids. Mol Membr Biol. 1994 Jul-Sep;11(3):181–187. doi: 10.3109/09687689409162237. [DOI] [PubMed] [Google Scholar]
  20. Ramprasad M. P., Fischer W., Witztum J. L., Sambrano G. R., Quehenberger O., Steinberg D. The 94- to 97-kDa mouse macrophage membrane protein that recognizes oxidized low density lipoprotein and phosphatidylserine-rich liposomes is identical to macrosialin, the mouse homologue of human CD68. Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9580–9584. doi: 10.1073/pnas.92.21.9580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Rigotti A., Acton S. L., Krieger M. The class B scavenger receptors SR-BI and CD36 are receptors for anionic phospholipids. J Biol Chem. 1995 Jul 7;270(27):16221–16224. doi: 10.1074/jbc.270.27.16221. [DOI] [PubMed] [Google Scholar]
  22. Sambrano G. R., Steinberg D. Recognition of oxidatively damaged and apoptotic cells by an oxidized low density lipoprotein receptor on mouse peritoneal macrophages: role of membrane phosphatidylserine. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1396–1400. doi: 10.1073/pnas.92.5.1396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Savill J. S., Henson P. M., Haslett C. Phagocytosis of aged human neutrophils by macrophages is mediated by a novel "charge-sensitive" recognition mechanism. J Clin Invest. 1989 Nov;84(5):1518–1527. doi: 10.1172/JCI114328. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Savill J., Dransfield I., Hogg N., Haslett C. Vitronectin receptor-mediated phagocytosis of cells undergoing apoptosis. Nature. 1990 Jan 11;343(6254):170–173. doi: 10.1038/343170a0. [DOI] [PubMed] [Google Scholar]
  25. Savill J., Fadok V., Henson P., Haslett C. Phagocyte recognition of cells undergoing apoptosis. Immunol Today. 1993 Mar;14(3):131–136. doi: 10.1016/0167-5699(93)90215-7. [DOI] [PubMed] [Google Scholar]
  26. 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. 1992 Oct;90(4):1513–1522. doi: 10.1172/JCI116019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Schlegel R. A., Reed J. A., McEvoy L., Algarin L., Williamson P. Phospholipid asymmetry of loaded red cells. Methods Enzymol. 1987;149:281–293. doi: 10.1016/0076-6879(87)49066-6. [DOI] [PubMed] [Google Scholar]
  28. Schlegel R. A., Stevens M., Lumley-Sapanski K., Williamson P. Altered lipid packing identifies apoptotic thymocytes. Immunol Lett. 1993 Jun;36(3):283–288. doi: 10.1016/0165-2478(93)90101-7. [DOI] [PubMed] [Google Scholar]
  29. Ugolini V., Nunez G., Smith R. G., Stastny P., Capra J. D. Initial characterization of monoclonal antibodies against human monocytes. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6764–6768. doi: 10.1073/pnas.77.11.6764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Verhoven B., Schlegel R. A., Williamson P. Mechanisms of phosphatidylserine exposure, a phagocyte recognition signal, on apoptotic T lymphocytes. J Exp Med. 1995 Nov 1;182(5):1597–1601. doi: 10.1084/jem.182.5.1597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Williamson P., Algarin L., Bateman J., Choe H. R., Schlegel R. A. Phospholipid asymmetry in human erythrocyte ghosts. J Cell Physiol. 1985 May;123(2):209–214. doi: 10.1002/jcp.1041230209. [DOI] [PubMed] [Google Scholar]

Articles from Molecular Biology of the Cell are provided here courtesy of American Society for Cell Biology

RESOURCES