Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 2002 Aug 15;366(Pt 1):195–201. doi: 10.1042/BJ20020045

Macrophage uptake of low-density lipoprotein bound to aggregated C-reactive protein: possible mechanism of foam-cell formation in atherosclerotic lesions.

Tao Fu 1, Jayme Borensztajn 1
PMCID: PMC1222776  PMID: 12033985

Abstract

Foam cells found in atherosclerotic lesions are believed to derive from macrophages that take up aggregated low-density lipoprotein (LDL) particles bound to the extracellular matrix of arterial walls. C-reactive protein (CRP) is an acute-phase protein found in atherosclerotic lesions, which when immobilized on a solid phase, can bind and cluster LDL particles in a calcium-dependent manner. In the present study, we examined whether CRP-bound aggregated LDL could be taken up by macrophages in culture. CRP molecules were aggregated in the presence of calcium and immobilized on the surface of polystyrene microtitre wells. Human LDL added to the wells bound to and aggregated on the immobilized CRP, also in a calcium-dependent manner. On incubation with macrophages, the immobilized CRP-bound LDL aggregates were readily taken up by the cells, as demonstrated by immunofluorescence microscopy, by the cellular accumulation of cholesterol and by the overexpression of adipophilin. Immunofluorescence microscopy and flow-cytometry analysis established that the uptake of the LDL-CRP complex was not mediated by the CRP receptor CD32. These observations with immobilized CRP and LDL, approximating the conditions that exist in the extracellular matrix of the arterial wall, thus suggest that CRP may contribute to the formation of foam cells in atherosclerotic lesions by causing the aggregation of LDL molecules that are then taken up by macrophages through a CD32-independent pathway.

Full Text

The Full Text of this article is available as a PDF (156.1 KB).

Selected References

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

  1. Amanuma K., Kanaseki T., Ikeuchi Y., Ohkuma S., Takano T. Studies on fine structure and location of lipids in quick-freeze replicas of atherosclerotic aorta of WHHL rabbits. Virchows Arch A Pathol Anat Histopathol. 1986;410(3):231–238. doi: 10.1007/BF00710829. [DOI] [PubMed] [Google Scholar]
  2. Bates S. R., Coughlin B. A., Mazzone T., Borensztajn J., Getz G. S. Apoprotein E mediates the interaction of beta-VLDL with macrophages. J Lipid Res. 1987 Jul;28(7):787–797. [PubMed] [Google Scholar]
  3. Bharadwaj D., Stein M. P., Volzer M., Mold C., Du Clos T. W. The major receptor for C-reactive protein on leukocytes is fcgamma receptor II. J Exp Med. 1999 Aug 16;190(4):585–590. doi: 10.1084/jem.190.4.585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Buechler C., Ritter M., Duong C. Q., Orso E., Kapinsky M., Schmitz G. Adipophilin is a sensitive marker for lipid loading in human blood monocytes. Biochim Biophys Acta. 2001 May 31;1532(1-2):97–104. doi: 10.1016/s1388-1981(01)00121-4. [DOI] [PubMed] [Google Scholar]
  5. Buton X., Mamdouh Z., Ghosh R., Du H., Kuriakose G., Beatini N., Grabowski G. A., Maxfield F. R., Tabas I. Unique cellular events occurring during the initial interaction of macrophages with matrix-retained or methylated aggregated low density lipoprotein (LDL). Prolonged cell-surface contact during which ldl-cholesteryl ester hydrolysis exceeds ldl protein degradation. J Biol Chem. 1999 Nov 5;274(45):32112–32121. doi: 10.1074/jbc.274.45.32112. [DOI] [PubMed] [Google Scholar]
  6. Du Clos T. W., Zlock L. T., Marnell L. Definition of a C-reactive protein binding determinant on histones. J Biol Chem. 1991 Feb 5;266(4):2167–2171. [PubMed] [Google Scholar]
  7. Faruqi R. M., DiCorleto P. E. Mechanisms of monocyte recruitment and accumulation. Br Heart J. 1993 Jan;69(1 Suppl):S19–S29. doi: 10.1136/hrt.69.1_suppl.s19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fleckenstein-Grün G., Fleckenstein A. Calcium--a neglected key factor in arteriosclerosis. The pathogenic role of arterial calcium overload and its prevention by calcium antagonists. Ann Med. 1991;23(5):589–599. doi: 10.3109/07853899109150522. [DOI] [PubMed] [Google Scholar]
  9. Kaplan M., Aviram M. Retention of oxidized LDL by extracellular matrix proteoglycans leads to its uptake by macrophages: an alternative approach to study lipoproteins cellular uptake. Arterioscler Thromb Vasc Biol. 2001 Mar;21(3):386–393. doi: 10.1161/01.atv.21.3.386. [DOI] [PubMed] [Google Scholar]
  10. Kruth H. S. Macrophage foam cells and atherosclerosis. Front Biosci. 2001 Mar 1;6:D429–D455. doi: 10.2741/kruth. [DOI] [PubMed] [Google Scholar]
  11. Lauer S., VanWye J., Harrison T., McManus H., Samuel B. U., Hiller N. L., Mohandas N., Haldar K. Vacuolar uptake of host components, and a role for cholesterol and sphingomyelin in malarial infection. EMBO J. 2000 Jul 17;19(14):3556–3564. doi: 10.1093/emboj/19.14.3556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lougheed M., Moore E. D., Scriven D. R., Steinbrecher U. P. Uptake of oxidized LDL by macrophages differs from that of acetyl LDL and leads to expansion of an acidic endolysosomal compartment. Arterioscler Thromb Vasc Biol. 1999 Aug;19(8):1881–1890. doi: 10.1161/01.atv.19.8.1881. [DOI] [PubMed] [Google Scholar]
  13. Nievelstein P. F., Fogelman A. M., Mottino G., Frank J. S. Lipid accumulation in rabbit aortic intima 2 hours after bolus infusion of low density lipoprotein. A deep-etch and immunolocalization study of ultrarapidly frozen tissue. Arterioscler Thromb. 1991 Nov-Dec;11(6):1795–1805. doi: 10.1161/01.atv.11.6.1795. [DOI] [PubMed] [Google Scholar]
  14. Pentikäinen M. O., Oörni K., Ala-Korpela M., Kovanen P. T. Modified LDL - trigger of atherosclerosis and inflammation in the arterial intima. J Intern Med. 2000 Mar;247(3):359–370. doi: 10.1046/j.1365-2796.2000.00655.x. [DOI] [PubMed] [Google Scholar]
  15. Pepys M. B., Rowe I. F., Baltz M. L. C-reactive protein: binding to lipids and lipoproteins. Int Rev Exp Pathol. 1985;27:83–111. [PubMed] [Google Scholar]
  16. Reynolds G. D., Vance R. P. C-reactive protein immunohistochemical localization in normal and atherosclerotic human aortas. Arch Pathol Lab Med. 1987 Mar;111(3):265–269. [PubMed] [Google Scholar]
  17. Shields M. J., Siegel J. N., Clark C. R., Hines K. K., Potempa L. A., Gewurz H., Anderson B. An appraisal of polystyrene-(ELISA) and nitrocellulose-based (ELIFA) enzyme immunoassay systems using monoclonal antibodies reactive toward antigenically distinct forms of human C-reactive protein. J Immunol Methods. 1991 Aug 9;141(2):253–261. doi: 10.1016/0022-1759(91)90152-6. [DOI] [PubMed] [Google Scholar]
  18. Torzewski J., Torzewski M., Bowyer D. E., Fröhlich M., Koenig W., Waltenberger J., Fitzsimmons C., Hombach V. C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries. Arterioscler Thromb Vasc Biol. 1998 Sep;18(9):1386–1392. doi: 10.1161/01.atv.18.9.1386. [DOI] [PubMed] [Google Scholar]
  19. Torzewski M., Rist C., Mortensen R. F., Zwaka T. P., Bienek M., Waltenberger J., Koenig W., Schmitz G., Hombach V., Torzewski J. C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis. Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):2094–2099. doi: 10.1161/01.atv.20.9.2094. [DOI] [PubMed] [Google Scholar]
  20. Wang X., Reape T. J., Li X., Rayner K., Webb C. L., Burnand K. G., Lysko P. G. Induced expression of adipophilin mRNA in human macrophages stimulated with oxidized low-density lipoprotein and in atherosclerotic lesions. FEBS Lett. 1999 Nov 26;462(1-2):145–150. doi: 10.1016/s0014-5793(99)01521-5. [DOI] [PubMed] [Google Scholar]
  21. Westhuyzen J., Healy H. Review: Biology and relevance of C-reactive protein in cardiovascular and renal disease. Ann Clin Lab Sci. 2000 Apr;30(2):133–143. [PubMed] [Google Scholar]
  22. Williams K. J., Tabas I. The response-to-retention hypothesis of atherogenesis reinforced. Curr Opin Lipidol. 1998 Oct;9(5):471–474. doi: 10.1097/00041433-199810000-00012. [DOI] [PubMed] [Google Scholar]
  23. Yasojima K., Schwab C., McGeer E. G., McGeer P. L. Generation of C-reactive protein and complement components in atherosclerotic plaques. Am J Pathol. 2001 Mar;158(3):1039–1051. doi: 10.1016/S0002-9440(10)64051-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Zwaka T. P., Hombach V., Torzewski J. C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation. 2001 Mar 6;103(9):1194–1197. doi: 10.1161/01.cir.103.9.1194. [DOI] [PubMed] [Google Scholar]
  25. de Beer F. C., Soutar A. K., Baltz M. L., Trayner I. M., Feinstein A., Pepys M. B. Low density lipoprotein and very low density lipoprotein are selectively bound by aggregated C-reactive protein. J Exp Med. 1982 Jul 1;156(1):230–242. doi: 10.1084/jem.156.1.230. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES