Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Feb 28;92(5):1396–1400. doi: 10.1073/pnas.92.5.1396

Recognition of oxidatively damaged and apoptotic cells by an oxidized low density lipoprotein receptor on mouse peritoneal macrophages: role of membrane phosphatidylserine.

G R Sambrano 1, D Steinberg 1
PMCID: PMC42526  PMID: 7877989

Abstract

We recently reported that oxidized low density lipoprotein (OxLDL), but not acetyl LDL (AcLDL), inhibited the binding and phagocytosis of nonopsonized, oxidatively damaged red blood cells (OxRBCs) by mouse peritoneal macrophages, implying the involvement of a "scavenger receptor" other than the AcLDL receptor. Numerous studies establish that loss of plasma membrane phospholipid asymmetry, which increases phosphatidylserine expression on the outer leaflet of the membrane, can play a key role in macrophage recognition of damaged and apoptotic cells. We report here that this recognition is in part attributable to the same mouse macrophage receptor that recognizes OxLDL. As described in an accompanying paper, this is a plasma membrane protein of 94-97 kDa. Phosphatidylserine liposomes show strong ligand binding to the same 94- to 97-kDa protein and this binding is inhibited by OxLDL but not by AcLDL. Inhibition of the RBC membrane phospholipid translocase by incubation with sodium vanadate caused a progressive increase in the appearance of phosphatidylserine on the cell surface and a parallel increase in the binding of these RBCs to macrophages, binding that was inhibited by OxLDL. Finally, OxLDL also inhibited the binding of sickled RBCs and apoptotic thymocytes to mouse macrophages. However, the latter was incomplete (approximately 50%), suggesting that other receptors are also involved. We suggest that the OxLDL receptor plays a significant role in recognition of damaged and apoptotic cells.

Full text

PDF
1396

Images in this article

1399Fig. 3
on p.1399

Selected References

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

  1. Abrams J. M., Lux A., Steller H., Krieger M. Macrophages in Drosophila embryos and L2 cells exhibit scavenger receptor-mediated endocytosis. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10375–10379. doi: 10.1073/pnas.89.21.10375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arai H., Kita T., Yokode M., Narumiya S., Kawai C. Multiple receptors for modified low density lipoproteins in mouse peritoneal macrophages: different uptake mechanisms for acetylated and oxidized low density lipoproteins. Biochem Biophys Res Commun. 1989 Mar 31;159(3):1375–1382. doi: 10.1016/0006-291x(89)92262-6. [DOI] [PubMed] [Google Scholar]
  3. Basu S. K., Goldstein J. L., Anderson G. W., Brown M. S. Degradation of cationized low density lipoprotein and regulation of cholesterol metabolism in homozygous familial hypercholesterolemia fibroblasts. Proc Natl Acad Sci U S A. 1976 Sep;73(9):3178–3182. doi: 10.1073/pnas.73.9.3178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Buttke T. M., Sandstrom P. A. Oxidative stress as a mediator of apoptosis. Immunol Today. 1994 Jan;15(1):7–10. doi: 10.1016/0167-5699(94)90018-3. [DOI] [PubMed] [Google Scholar]
  5. Carew T. E., Schwenke D. C., Steinberg D. Antiatherogenic effect of probucol unrelated to its hypocholesterolemic effect: evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7725–7729. doi: 10.1073/pnas.84.21.7725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cohen J. J. Apoptosis. Immunol Today. 1993 Mar;14(3):126–130. doi: 10.1016/0167-5699(93)90214-6. [DOI] [PubMed] [Google Scholar]
  7. Devaux P. F. Protein involvement in transmembrane lipid asymmetry. Annu Rev Biophys Biomol Struct. 1992;21:417–439. doi: 10.1146/annurev.bb.21.060192.002221. [DOI] [PubMed] [Google Scholar]
  8. Endemann G., Stanton L. W., Madden K. S., Bryant C. M., White R. T., Protter A. A. CD36 is a receptor for oxidized low density lipoprotein. J Biol Chem. 1993 Jun 5;268(16):11811–11816. [PubMed] [Google Scholar]
  9. 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]
  10. 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]
  11. Freeman M., Ekkel Y., Rohrer L., Penman M., Freedman N. J., Chisolm G. M., Krieger M. Expression of type I and type II bovine scavenger receptors in Chinese hamster ovary cells: lipid droplet accumulation and nonreciprocal cross competition by acetylated and oxidized low density lipoprotein. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4931–4935. doi: 10.1073/pnas.88.11.4931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. HAVEL R. J., EDER H. A., BRAGDON J. H. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest. 1955 Sep;34(9):1345–1353. doi: 10.1172/JCI103182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Henriksen T., Mahoney E. M., Steinberg D. Enhanced macrophage degradation of low density lipoprotein previously incubated with cultured endothelial cells: recognition by receptors for acetylated low density lipoproteins. Proc Natl Acad Sci U S A. 1981 Oct;78(10):6499–6503. doi: 10.1073/pnas.78.10.6499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Krieger M., Acton S., Ashkenas J., Pearson A., Penman M., Resnick D. Molecular flypaper, host defense, and atherosclerosis. Structure, binding properties, and functions of macrophage scavenger receptors. J Biol Chem. 1993 Mar 5;268(7):4569–4572. [PubMed] [Google Scholar]
  15. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  16. Lee K. D., Pitas R. E., Papahadjopoulos D. Evidence that the scavenger receptor is not involved in the uptake of negatively charged liposomes by cells. Biochim Biophys Acta. 1992 Oct 19;1111(1):1–6. doi: 10.1016/0005-2736(92)90267-p. [DOI] [PubMed] [Google Scholar]
  17. Lennon S. V., Martin S. J., Cotter T. G. Dose-dependent induction of apoptosis in human tumour cell lines by widely diverging stimuli. Cell Prolif. 1991 Mar;24(2):203–214. doi: 10.1111/j.1365-2184.1991.tb01150.x. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Morel D. W., Hessler J. R., Chisolm G. M. Low density lipoprotein cytotoxicity induced by free radical peroxidation of lipid. J Lipid Res. 1983 Aug;24(8):1070–1076. [PubMed] [Google Scholar]
  20. Morrot G., Zachowski A., Devaux P. F. Partial purification and characterization of the human erythrocyte Mg2(+)-ATPase. A candidate aminophospholipid translocase. FEBS Lett. 1990 Jun 18;266(1-2):29–32. doi: 10.1016/0014-5793(90)81498-d. [DOI] [PubMed] [Google Scholar]
  21. Nishikawa K., Arai H., Inoue K. Scavenger receptor-mediated uptake and metabolism of lipid vesicles containing acidic phospholipids by mouse peritoneal macrophages. J Biol Chem. 1990 Mar 25;265(9):5226–5231. [PubMed] [Google Scholar]
  22. Op den Kamp J. A. Lipid asymmetry in membranes. Annu Rev Biochem. 1979;48:47–71. doi: 10.1146/annurev.bi.48.070179.000403. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Pradhan D., Weiser M., Lumley-Sapanski K., Frazier D., Kemper S., Williamson P., Schlegel R. A. Peroxidation-induced perturbations of erythrocyte lipid organization. Biochim Biophys Acta. 1990 Apr 30;1023(3):398–404. doi: 10.1016/0005-2736(90)90132-8. [DOI] [PubMed] [Google Scholar]
  25. Sambrano G. R., Parthasarathy S., Steinberg D. Recognition of oxidatively damaged erythrocytes by a macrophage receptor with specificity for oxidized low density lipoprotein. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3265–3269. doi: 10.1073/pnas.91.8.3265. [DOI] [PMC free article] [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. Schroit A. J., Madsen J. W., Tanaka Y. In vivo recognition and clearance of red blood cells containing phosphatidylserine in their plasma membranes. J Biol Chem. 1985 Apr 25;260(8):5131–5138. [PubMed] [Google Scholar]
  28. Schwartz R. S., Tanaka Y., Fidler I. J., Chiu D. T., Lubin B., Schroit A. J. Increased adherence of sickled and phosphatidylserine-enriched human erythrocytes to cultured human peripheral blood monocytes. J Clin Invest. 1985 Jun;75(6):1965–1972. doi: 10.1172/JCI111913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sparrow C. P., Parthasarathy S., Steinberg D. A macrophage receptor that recognizes oxidized low density lipoprotein but not acetylated low density lipoprotein. J Biol Chem. 1989 Feb 15;264(5):2599–2604. [PubMed] [Google Scholar]
  30. Steinberg D. Arterial metabolism of lipoproteins in relation to atherogenesis. Ann N Y Acad Sci. 1990;598:125–135. doi: 10.1111/j.1749-6632.1990.tb42284.x. [DOI] [PubMed] [Google Scholar]
  31. Steinberg D. Arterial metabolism of lipoproteins in relation to atherogenesis. Ann N Y Acad Sci. 1990;598:125–135. doi: 10.1111/j.1749-6632.1990.tb42284.x. [DOI] [PubMed] [Google Scholar]
  32. Steinbrecher U. P., Parthasarathy S., Leake D. S., Witztum J. L., Steinberg D. Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci U S A. 1984 Jun;81(12):3883–3887. doi: 10.1073/pnas.81.12.3883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Tait J. F., Gibson D. Measurement of membrane phospholipid asymmetry in normal and sickle-cell erythrocytes by means of annexin V binding. J Lab Clin Med. 1994 May;123(5):741–748. [PubMed] [Google Scholar]
  34. Tanaka Y., Schroit A. J. Insertion of fluorescent phosphatidylserine into the plasma membrane of red blood cells. Recognition by autologous macrophages. J Biol Chem. 1983 Sep 25;258(18):11335–11343. [PubMed] [Google Scholar]
  35. Ylä-Herttuala S., Palinski W., Rosenfeld M. E., Parthasarathy S., Carew T. E., Butler S., Witztum J. L., Steinberg D. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest. 1989 Oct;84(4):1086–1095. doi: 10.1172/JCI114271. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES