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Phagocytosis and clearance of apoptotic cells is mediated by MER

Nature volume 411, pages 207–211 (2001)Cite this article

Abstract

Apoptosis is fundamental to the development and maintenance of animal tissues and the immune system1. Rapid clearance of apoptotic cells by macrophages is important to inhibit inflammation and autoimmune responses against intracellular antigens2,3,4. Here we report a new function for Mer, a member of the Axl/Mer/Tyro3 receptor tyrosine kinase family. merkd mice with a cytoplasmic truncation of Mer had macrophages deficient in the clearance of apoptotic thymocytes. This was corrected in chimaeric mice reconstituted with bone marrow from wild-type animals. Primary macrophages isolated from merkd mice showed that the phagocytic deficiency was restricted to apoptotic cells and was independent of Fc receptor-mediated phagocytosis or ingestion of other particles. The inability to clear apoptotic cells adequately may be linked to an increased number of nuclear autoantibodies in merkd mice. Thus, the Mer receptor tyrosine kinase seems to be critical for the engulfment and efficient clearance of apoptotic cells. This has implications for inflammation and autoimmune diseases such as systemic lupus erythematosus.

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Figure 1: Effect of bone marrow reconstitution on dexamethasone treatment of thymus.
Figure 2: Macrophage phagocytosis of apoptotic thymocytes from merkd and wild-type mice.
Figure 3: Binding of apoptotic thymocytes to wild-type and merkd macrophages.
Figure 4: Phagocytosis of opsonized thymocytes.

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References

  1. Jacobson, M. D., Weil, M. & Raff, M. C. Programmed cell death in animal development. Cell 88, 347–354 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Casiano, C. A. & Tan, E. M. Recent developments in the understanding of antinuclear autoantibodies. Int. Atch. Allergy Immunol. 111, 308–313 (1996).

    Article  CAS  Google Scholar 

  4. Rosen, A. & Casciola-Rosen, L. Autoantigens as substrates for apoptotic proteases: implications for the pathogenesis of systemic autoimmune disease. Cell Death Diff. 6, 6–12 (1999).

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  6. 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  Google Scholar 

  7. Fadok, V. A. et al. A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405, 85–90 (2000).

    Article  ADS  CAS  Google Scholar 

  8. 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 

  9. Savill, J., Hogg, N., Ren, Y. & Haslett, C. Thombospondin cooperates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. J. Clin. Invest. 90, 1513–1521 (1992).

    Article  CAS  Google Scholar 

  10. Stern, M., Savill, J. & Haslett, C. Human monocyte-derived macrophage phagocytosis of senescent eosinophils undergoing apoptosis. Mediation by alpha v beta3/CD36/thrombospondin recognition mechanism and lack of phlogistic response. Am. J. Pathol. 149, 911–921 (1996).

    CAS  Google Scholar 

  11. Devitt, A. et al. Human CD14 mediates recognition and phagocytosis of apoptotic cells. nature 392, 505–509 (1998).

    Article  ADS  CAS  Google Scholar 

  12. Taylor, P. R. et al. A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J. Exp. Med. 192, 359–366 (2000).

    Article  CAS  Google Scholar 

  13. O'Bryan, J. P. et al. ax1, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. Mol. Cell Biol. 11, 5016-5031 (1991).

    Article  Google Scholar 

  14. Lai, C., Gore, M. & Lemke, G. Structure, expression, and activity of Tyro 3, a neural adhesion-related receptor tyrosine kinase. Oncogene 9, 2567–2578 (1994).

    CAS  Google Scholar 

  15. Graham, D. K. et al. Cloning and development expression analysis of the murine c-mer tyrosine kinase. Oncogene 10, 2349–2359 (1995).

    CAS  Google Scholar 

  16. McCloskey, P. et al. GAS6 mediates adhesion of cells expressing the receptor tyrosine kinase Axl. J. Biol. Chem. 272, 23285–23291 (1997).

    Article  CAS  Google Scholar 

  17. Fridell, Y. W., Villa, J. J., Attar, E. C. & Liu, E. T. GAS6 induces Ax1-mediated chemotaxis of vascular smooth muscle cells. J. Biol. Chem. 273, 7123–7126 (1998).

    Article  CAS  Google Scholar 

  18. Camenisch, T. D., Koller, B. H., Earp, H. S. & Matsushima, G. K. A novel receptor tyrosine kinase, Mer, inhibits TNF-α production and lipopolysaccharide-induced endotoxic shock. J. Immunol. 162, 3498–3503 (1999).

    CAS  Google Scholar 

  19. Nagata, K. et al. Identification of the product of growth arrest-specific gene 6 as a common ligand for Axl, Sky, and Mer receptor tyrosine kinases. J. Biol. Chem. 271, 30022–30027 (1996).

    Article  CAS  Google Scholar 

  20. Nakano, T. et al. Cell adhesion to phosphatidylserine mediated by a product of growth arrest-specific gene 6. J. Biol. Chem. 272, 29411–29414 (1997).

    Article  CAS  Google Scholar 

  21. Reap, E. A. et al. Radiation and stress-induced apoptosis: A role for Fas/Fas ligand interactions. Proc. Natl Acad. Sci. USA 94, 5750–5755 (1997).

    Article  ADS  CAS  Google Scholar 

  22. Licht, R., Jacobs, C. W. M., Tax, W. J. M. & Berden, J. H. M. An assay for the quantitative measurement of in vitro phagocytosis of early apoptotic thymocytes by murine resident peritoneal macrophages. J. Immunol. Methods 223, 237–248 (1999).

    Article  CAS  Google Scholar 

  23. Mervorach, D., Zhou, J. L., Song, X. & Elkon, K. B. Systemic exposure to irradiated apoptotic cells induces autoantibody production. J. Exp. Med. 188, 387–392 (1998).

    Article  Google Scholar 

  24. Meryhew, H. L., Shaver, C., Messner, R. P. & Runquist, O. A. Mononuclear phagocyte system dysfunction in murine SLE: abnormal clearance kinetics precede clinical disease. J. Lab. Clin. Med. 117, 181–193 (1991).

    CAS  Google Scholar 

  25. Aguilar, L. K., Aguilar-Cordova, E., Cartwright, J. & Belmont, J. W. Thymic nurse cells are sites of thymocyte apoptosis. J. Immunol. 152, 2645–2651 (1994).

    CAS  Google Scholar 

  26. D'Cruz, P. M. et al. Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Human Mol. Genet. 9, 645–651 (2000).

    Article  CAS  Google Scholar 

  27. Gal, A. et al. Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nature Med. 26, 270–271 (2000).

    Article  CAS  Google Scholar 

  28. Lu, Q. et al. Tyro-3 family receptors are essential regulators of mammalian spermatogenesis. Nature 398, 723–728 (1999).

    Article  ADS  CAS  Google Scholar 

  29. Hsu, S. & Ree, H. J. Histochemical studies on lectin binding in reactive lymphoid tissues. J. Histochem. Cytochem. 31, 538–546 (1983).

    Article  CAS  Google Scholar 

  30. Eisenberg, R. A., Winfield, J. B. & Cohen, P. L. Subclass restriction of anti-Sm antibodies in MRL mice. J. Immunol. 129, 2146–2149 (1982).

    CAS  Google Scholar 

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Acknowledgements

We thank R. Bagnell and V. Madden for assistance with microscopy, C. Lawler for statistical analysis, E. Cash and T. Lee for histological assistance, S. Parker for irradiating mice and L. Su for critical reading of the manuscript.

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Author notes

  1. Rona S. Scott

    Present address: Louisiana State University, Health Sciences Center, Shreveport, Louisiana, USA

Authors and Affiliations

  1. UNC Neuroscience Center,

    Rona S. Scott & Glenn K. Matsushima

  2. Department of Microbiology and Immunology,

    Eileen J. McMahon & Glenn K. Matsushima

  3. Curriculum in Oral Biology,

    Shannon M. Pop & Glenn K. Matsushima

  4. Department of Pharmacology and Lineberger Comprehensive Cancer Center,

    H. Shelton Earp

  5. Comprehensive Center for Inflammatory Disorders and Program for Molecular Biology and Biotechnology, University of North Carolina at Chapel Hill, 27599, North Carolina, USA

    Glenn K. Matsushima

  6. Alphavax Human Vaccines, Durham, 27701, North Carolina, USA

    Elizabeth A. Reap

  7. Department of Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Roberto Caricchio & Philip L. Cohen

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Correspondence to Glenn K. Matsushima.

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Scott, R., McMahon, E., Pop, S. et al. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411, 207–211 (2001). https://doi.org/10.1038/35075603

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