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Recognition by Macrophages and Liver Cells of Opsonized Phospholipid Vesicles and Phospholipid Headgroups

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Abstract

The interaction of liposomes with blood proteins is believed to play a critical role in the clearance pharmacokinetics and tissue distribution of intravenously injected liposomes. In this article we have focused our discussion on the interaction of liposomes with key blood proteins, which include immunoglobulins, complement proteins, apolipoproteins, fetuin, von Willebrand factor, and thrombospondin, and their role in liposome recognition by professional phagocytes and nonmacrophage hepatic cells. Alternatively, macrophages as well as hepatocytes and liver endothelial cells may phagocytose/endocytose liposomes via direct recognition of phospholipid headgroups. A number of plasma membrane receptors such as lectin receptors, CD14, various classes of scavenger receptors (e.g., classes A, B, and D), FcγRI and FcγRII-B2 may participate in phospholipid recognition. These concepts are also discussed.

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REFERENCES

  1. S. C. Semple, A. Chonn, and P. R. Cullis. Interactions of liposomes and lipid-based carrier systems with blood proteins: Relation to clearance behaviour in vivo. Adv. Drug Deliv. Rev. 32:3-17 (1998).

    Google Scholar 

  2. F. Bonté and R. L. Juliano. Interactions of liposomes with serum proteins. Chem. Phys. Lipids 40:359-372 (1986).

    Google Scholar 

  3. S. M. Moghimi and H. M. Patel. Tissue specific opsonins for phagocytic cells and their different affinity for cholesterol-rich liposomes. FEBS Lett. 233:143-147 (1988).

    Google Scholar 

  4. A. Chonn, S. C. Semple, and P. R. Cullis. Association of blood proteins with large unilamellar liposomes in vivo. Relation to circulation lifetimes. J. Biol. Chem. 267:18759-18765 (1992).

    Google Scholar 

  5. A. Chonn, P. R. Cullis, and D. V. Devine. The role of surface charge in the activation of the classical and alternative pathways of complement by liposomes. J. Immunol. 146:4234-4241 (1991).

    Google Scholar 

  6. E. T. M. Dams, P. Laverman, W. J. G. Oyen, G. Storm, G. L. Scherphof, J. W. M. Van Der Meer, F. H. Corstens, and O. C. Boerman. Accelerated blood clearance and altered biodistribution of repeated injections of sterically stabilized liposomes. J. Pharmacol. Exp. Ther. 292:1071-1079 (2000).

    Google Scholar 

  7. H. M. Patel. Serum opsonins and liposomes: Their interaction and opsonophagocytosis. Crit. Rev. Ther. Drug Carrier Syst. 9: 39-90 (1992).

    Google Scholar 

  8. C. R. Alving and G. M. Swartz, Jr. Antibodies to cholesterol, cholesterol conjugates and liposomes: Implications for atherosclerosis and autoimmunity. CRC Crit. Rev. Immunol. 10:441-453 (1991).

    Google Scholar 

  9. S. Hörkkö, E. Miller, D. Ware Branch, W. Palinski, and J. L. Witztum. The epitopes for some antiphospholipid antibodies are adducts of oxidized phospholipid and β2 glycoprotein 1 (and other proteins). Proc. Natl. Acad. Sci. USA 94:10356-10361 (1997).

    Google Scholar 

  10. S. M. Moghimi and S. S. Davis. Innovations in avoiding particles clearance from blood by Kupffer cells: Cause for reflection. Crit. Rev. Ther. Drug Carrier Syst. 11:31-59 (1994).

    Google Scholar 

  11. S. M. Moghimi and H. M. Patel. Serum-mediated recognition of liposomes by phagocytic cells of the reticuloendothelial system—The concept of tissue specificity. Adv. Drug Deliv. Rev. 32:45-60 (1998).

    Google Scholar 

  12. M. Tomita, K. Yamamoto, H. Kobashi, M. Ohmoto, and T. Tsuji. Immunohistochemical phenotyping of liver macrophages in normal and diseased human liver. Hepatology 20:317-325 (1994).

    Google Scholar 

  13. D. V. Devine and J. M. J. Marjan. The role of immunoproteins in the survival of liposomes in the circulation. Crit. Rev. Ther. Drug Carr. Syst. 14:105-131 (1997).

    Google Scholar 

  14. J. Szebeni. The interaction of liposomes with the complement system. Crit. Rev. Ther. Drug Carr. Syst. 15:57-89 (1998).

    Google Scholar 

  15. K. Funato, R. Yoda, and H. Kiwada. Contribution of complement system on destabilization of liposomes composed of hydrogenated egg phosphatidylcholine in fresh rat plasma. Biochim. Biophys. Acta 1103:198-204 (1992).

    Google Scholar 

  16. J. Marjan, Z. Xie, and D. V. Devine. Liposome-induced activation of the classical complement pathway does not require immunoglobulin. Biochim. Biophys. Acta 1192:35-44 (1994).

    Google Scholar 

  17. A. J. Bradley, E. Maurer Spurej, D. E. Brooks, and D. V. Devine. Unusual electrostatic effects on binding of C1q to anionic liposomes: Role of anionic phospholipid domains and their line tension. Biochemistry 38:8112-8123 (1999).

    Google Scholar 

  18. A. J. Bradley, D. V. Devine, S. M. Ansell, J. Janzen, and D. E. Brooks. Inhibition of liposome-induced complement activation by incorporated poly(ethylene glycol)-lipids. Arch. Biochem. Biophys. 357:185-194 (1998).

    Google Scholar 

  19. R. L. Richards, H. Gewurz, A. P. Osmand, and C. R. Alving. Interactions of C-reactive protein and complement with liposomes. Proc. Natl. Acad. Sci. USA 74:5672-5680 (1977).

    Google Scholar 

  20. D. V. Devine, K. Wong, K. Serrano, A. Chonn, and P. R. Cullis. Liposome-complement interactions in rat serum: Implications for liposome survival studies. Biochim. Biophys. Acta 1191:43-51 (1994).

    Google Scholar 

  21. Y. Kuroki, T. Honma, H. Chiba, H. Sano, M. Saitoh, Y. Ogasawara, H. Sohma, and T. Akino. A novel type of binding specificity to phospholipids of rat mannose-binding proteins isolated from serum and liver. FEBS Lett. 414:387-392 (1997).

    Google Scholar 

  22. M. Kuhlman, K. Joiner, and R. A. Ezekowitz. The human mannose-binding protein functions as an opsonin. J. Exp. Med. 169: 1733-1741 (1989).

    Google Scholar 

  23. J. E. Volanakis, and K. W. A. Wirtz. Interaction of C-reactive protein with artificial phosphatidylcholine bilayers. Nature 281: 155-157 (1979).

    Google Scholar 

  24. U. R. Nilsson, K. E. Storm, H. Elwing, and B. Nilsson. Conformational epitopes of C3 reflecting its mode of binding to an artificial polymer surface. Mol. Immunol. 30:211-219 (1993).

    Google Scholar 

  25. H. Harashima, K. Sakata, K. Funato, and H. Kiwada. Enhanced hepatic uptake of liposomes through complement activation depending on the size of liposomes. Pharm. Res. 11:402-406 (1994).

    Google Scholar 

  26. H. Harashima, M. Matsuo, and H. Kiwada. Identification of proteins mediating clearance of liposomes using a liver perfusion system. Adv. Drug Deliv. Rev. 32:61-79 (1998).

    Google Scholar 

  27. S. R. Barnum, J. L. Jones, U. Mullerladner, A. Samimi, and I. L. Campbell. Chronic complement C3 gene expression in the CNS of transgeneic mice with astrocyte-targeted interleukin-6 expression. Glia 18:107-117 (1996).

    Google Scholar 

  28. H. C. Loughrey, M. B. Bally, L. W. Reinish, and P. R. Cullis. The binding of phosphatidylglycerol liposomes to rat platelets is mediated by complement. Throm. Haemost. 64:172-176 (1990).

    Google Scholar 

  29. W. V. Rodrigueza, M. C. Phillips, and K. J. Williams. Structural and metabolic consequences of liposome-lipoprotein interactions. Adv. Drug Deliv. Rev. 32:31-43 (1998).

    Google Scholar 

  30. J. L. Breslow. Mouse models of atherosclerosis. Science 272:685-688 (1996).

    Google Scholar 

  31. G. L. Scherphof, and J. A. A. M. Kamps. Receptor versus non-receptor mediated clearance of liposomes. Adv. Drug Deliv. Rev. 32:81-97 (1998).

    Google Scholar 

  32. A. Chonn, S. C. Semple, and P. R. Cullis. β2-Glycoprotein I is a major protein associated with very rapidly cleared liposomes in vivo, suggesting a significant role in the immune clearance of ‘non-self’ particles. J. Biol. Chem. 270:25845-25849 (1995).

    Google Scholar 

  33. T. Ishida, K. Funato, S. Kojima, R. Yoda, and H. Kiwada. Enhancing effect of cholesterol on the elimination of liposomes from circulation is mediated by complement activation. Int. J. Pharmaceut. 156:27-37 (1997).

    Google Scholar 

  34. T. M. Huong, H. Harashima, and H. Kiwada. In vivo studies on the role of complement in the clearance of liposomes in rats and guinea pigs. Biol. Pharm. Bull. 22:515-520 (1999).

    Google Scholar 

  35. S. M. Moghimi. Opsono-recognition of liposomes by tissue macrophages. Int. J. Pharmaceut. 162:11-18 (1998).

    Google Scholar 

  36. S. M. Moghimi and H. M. Patel. Differential properties of organ-specific serum opsonins for liver and spleen macrophages. Biochim. Biophys. Acta 984:379-383 (1989).

    Google Scholar 

  37. S. M. Moghimi and H. M. Patel. Calcium as a possible modulator of Kupffer cell phagocytic function by regulating liver-specific opsonic activity. Biochim. Biophys. Acta 1028:304-308 (1990).

    Google Scholar 

  38. S. M. Moghimi and H. M. Patel. Altered tissue-specific opsonic activities and opsono-recognition of liposomes in tumour-bearing rats. Biochim. Biophys. Acta 1285:56-64 (1996).

    Google Scholar 

  39. J. T. P. Derksen, J. D. Baldeschwieler, and G. L. Scherphof. In vivo stability of ester-and ether-linked phospholipid-containing liposomes as measured by perturbed angular correlation spectroscopy. Proc. Natl. Acad. Sci. USA 85:9768-9772 (1988).

    Google Scholar 

  40. C. L. Bisgaier, M. V. Siebenkas, and K. J. Williams. Effects of apolipoproteins A-IV and A-I on the uptake of phospholipid liposomes by hepatocytes. J. Biol. Chem. 264:862-866 (1989).

    Google Scholar 

  41. H. Wang, M. Zhang, M. Bianchi, B. Sherry, A. Sama, and K. J. Tracey. Fetuin (α2-HS-glycoprotein) opsonizes cationic macrophage-deactivating molecules. Proc. Natl. Acad. Sci. USA 95: 14429-14434 (1998).

    Google Scholar 

  42. M. V. Serra, F. Mannu, A. Matera, F. Turrini, and P. Arese. Enhanced IgG-and complement-independent phagocytosis of sulfatide-enriched human erythrocytes by human monocytes. FEBS Lett. 311:67-70 (1992).

    Google Scholar 

  43. J. S. Savill, P. M. Henson, and C. Haslett. Thrombospondin cooperates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. J. Clin. Invest. 90:1513-1522 (1992).

    Google Scholar 

  44. F. Liu and D. Liu. Serum independent liposome uptake by mouse liver. Biochim. Biophys. Acta 1278:5-11 (1996).

    Google Scholar 

  45. Q. Hu and D. Liu. Co-existance of serum-dependent and serum-independent mechanism for liposome clearance and involvement of non-Kupffer cells in liposome uptake by mouse liver. Biochim. Biophys. Acta 1284:153-161 (1996).

    Google Scholar 

  46. K. D. Lee, K. Hong, and D. Papahadjopoulos. Recognition of liposomes by cell: in vitro binding and endocytosis mediated by specific lipid head groups and surface charge density. Biochim. Biophys. Acta 1103:185-197 (1992).

    Google Scholar 

  47. R. P. da Silva, N. Platt, W. J. S. de Villiers, and S. Gordon. Membrane molecules and macrophage endocytosis: scavenger receptor and macrosialin as markers of plasma-membrane and vacuolar functions. Biochem. Soc. Trans. 24:220-224 (1996).

    Google Scholar 

  48. D. R. Greaves, P. J. Gough, and S. Gordon. Recent progress on defining the role of scavenger receptors in lipid transport, atherosclerosis and host defence. Curr. Opin. Lipidol. 9:425-432 (1998).

    Google Scholar 

  49. T. Kodama, T. Doi, H. Suzuki, K. Takahashi, Y. Wada, and S. Gordon. Collagenous macrophage scavenger receptors. Curr. Opin. Lipidol. 7:287-291 (1996).

    Google Scholar 

  50. S. Acton, D. Resnick, M. Freeman, Y. Ekkel, J. Askenas, and M. Krieger. The collagenous domains of macrophage scavenger receptors and complement component C1q mediate similar, but not identical, binding specificities for polyanionic ligands. J. Biol. Chem. 268:3530-3537 (1993).

    Google Scholar 

  51. O. Elomaa, M. Kangas, C. Sahlberg, J. Tuukkanen, R. Sormunen, A. Liakka, I. Thesleff, G. Kraal, and K. Tryggvason. Cloning of a novel bacteria-binding receptor structurally related to scavenger receptors and expressed in a subset of macrophages. Cell 80:603-609 (1995).

    Google Scholar 

  52. J. Dijkstra, M. Van Galen, and G. Scherphof. Influence of liposome charge on the association of liposomes with Kupffer cells in vitro. Effects of divalent cations and competition with latex particles. Biochim. Biophys. Acta 813:287-297 (1985).

    Google Scholar 

  53. J. A. A. M. Kamps, H. W. M. Morselt, and G. L. Scherphof. Uptake of liposomes containing phosphatidylserine by liver cells in vivo and by sinusoidal liver cells in primary culture: In vivo-in vitro differences. Biochem. Biophys. Res. Commun. 256:57-62 (1999).

    Google Scholar 

  54. K. Nishikawa, H. Arai, and K. Inoue. Scavenger receptor-mediated uptake and metabolism of lipid vesicles containing acidic phospholipids by mouse peritoneal macrophages. J. Biol. Chem. 265:5226-5231 (1990).

    Google Scholar 

  55. H. Suzuki, Y. Kurihara, M. Takeya, N. Kamada, M. Kataoka, K. Jishage, O. Ueda, H. Sakaguchi, T. Higashi, T. Suzuki, Y. Takashima, Y. Kawabe, O. Cynshi, Y. Wada, M. Hondo, H. Kurihara, H. Aburatani, T. Doi, A. Matsumoto, S. Azuma, T. Noda, Y. Toyoda, H. Itakura, Y. Yazaki, S. Horiuchi, K. Takahashi, J. Kar Kruijt, T. J. C. van Berkel, R. P. Steinbrecher, S. Ishibashi, N. Maeda, S. Gordon, and T. Kodama. A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection. Nature 386:292-296 (1997).

    Google Scholar 

  56. V. A. Fadok, D. R. Voelker, P. A. Campbell, J. J. Cohen, D. L. Bratton, and P. M. Henson. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J. Immunol. 148:2207-2216 (1992).

    Google Scholar 

  57. G. Endemann, L. W. Stanton, K. S. Madden, C. M. Bryant, R. Tyler White, and A. A. Protter. CD36 is a receptor for oxidized low density lipoprotein. J. Biol. Chem. 268:11811-11816 (1993).

    Google Scholar 

  58. M. Fukasawa, H. Adachi, K. Hirota, M. Tsujimoto, H. Arai, and K. Inoue. SRB1, a class B scavenger receptor, recognizes both negatively charged liposomes and apoptotic cells. Exp. Cell Res. 222:246-250 (1996).

    Google Scholar 

  59. K. Fluiter and T. J. C. van Berkel. Scavenger receptor B1 (SRB1) substrates inhibit the selective uptake of high-density-lipoprotein cholesteryl esters by rat parenchymal liver cells. Biochem. J. 326:515-519 (1997).

    Google Scholar 

  60. M. Lougheed, C. M. Lum, W. H. Ling, H. Suzuki, T. Kodama, and U. Steinbrecher. High affinity saturable uptake of oxidized low density lipoprotein by macrophages from mice lacking the scavenger class A type I/II. J. Biol. Chem. 272:12938-12944 (1997).

    Google Scholar 

  61. A. G. van Velzen, R. P. Da Silva, S. Gordon, and T. J. C. van Berkel. Characterization of a receptor for oxidized low-density lipoproteins on rat Kupffer cells: Similarity to macrosialin. Biochem. J. 322:411-415 (1997).

    Google Scholar 

  62. T. Sawamura, N. Kume, T. Aoyama, H. Moriwaki, H. Hoshikawa, Y. Aiba, T. Tanaka, S. Miwa, Y. Katsura, T. Kita, and T. Masaki. An endothelial receptor for oxidized low-density lipoprotein. Nature 386:73-77 (1977).

    Google Scholar 

  63. H. Adachi, M. Tsujimoto, H. Arai, and K. Inoue. Expression cloning of a novel scavenger receptor from human endothelial cells. J. Biol. Chem. 272:31217-31220 (1998).

    Google Scholar 

  64. Y. B. de Rijke and T. J. C. van Berkel. Rat liver Kupffer and endothelial cells express different binding proteins for modified low density lipoproteins. J. Biol. Chem. 269:824-827 (1994).

    Google Scholar 

  65. M. Nagase, S. Hirose, T. Sawamura, T. Masaki, and T. Fujita. Enhanced expression of endothelial oxidized low-density lipoprotein receptor (LOX-1) in hypertensive rats. Biochem. Biophys. Res. Commun. 237:496-498 (1997).

    Google Scholar 

  66. F. G. Blankenberg, P. D. Katsikis, J. F. Tait, R. E. Davis, L. Naumovski, K. Ohtsuki, S. Kopiwoda, M. J. Abrams, M. Darkes, R. C. Robbins, H. T. Maecker, and H. W. Strauss. In vivo detection and imaging of phosphatidylserine expression during programmed cell death. Proc. Natl. Acad. Sci. USA 95:6349-6354 (1998).

    Google Scholar 

  67. J. A. A. M. Kamps, H. W. M. Morselt, P. J. Swart, D. K. F. Meijer, and G. L. Scherphof. Massive targeting of liposomes, surface-modified with anionized albumins, to hepatic endothelial cells. Proc. Natl. Acad. Sci. USA 94:11681-11685 (1997).

    Google Scholar 

  68. L. W. Stanton, R. T. White, C. M. Bryant, A. Protter, and G. Endemann. A macrophage Fc receptor for IgG is also a receptor for oxidized low-density-lipoprotein. J. Biol. Chem. 267:22446-22451 (1992).

    Google Scholar 

  69. H. Arai, T. Kita, M. Yokode, S. Narumiya, and C. Kawai. 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. 159:1375-1382 (1989).

    Google Scholar 

  70. A. Devitt, O. D. Moffatt, C. Raykundalia, J. D. Capra, D. L. Simmons, and C. D. Gregory. Human CD14 mediates recognition and phagocytosis of apoptotic cells. Nature 392:505-509 (1998).

    Google Scholar 

  71. S. M. Moghimi. Hormonal-control of macrophage phagocytosis of phospholipid vesicles. J. Liposome Res. 10:379-387 (2000).

    Google Scholar 

  72. J. F. Bohnsack, J. J. Oshea, T. Takahashi, and E. J. Brown. Fibronectin-enhanced phagocytosis of an alternative pathway activator by human culture-derived macrophages is mediated by the C4B/C3B complement receptor (CR-1). J. Immunol. 135:2680-2686 (1985).

    Google Scholar 

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  1. Molecular Targeting and Polymer Toxicology Group, School of Pharmacy and Biomolecular Sciences, University of Brighton, Cockcroft Building, Brighton, BN2 4GJ, U.K.

    S. Moein Moghimi & A. Christy Hunter

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Moghimi, S.M., Hunter, A.C. Recognition by Macrophages and Liver Cells of Opsonized Phospholipid Vesicles and Phospholipid Headgroups. Pharm Res 18, 1–8 (2001). https://doi.org/10.1023/A:1011054123304

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