Skip to main content
Log in

Phagocytosis of Myelin in Demyelinative Disease: A Review

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

In the cell-mediated demyelinating diseases such as experimental allergic encephalomyelitis and multiple sclerosis, as well as their peripheral nerve counterparts, the phagocytic cells are the agent of myelin destruction. Both resident microglia and peripheral macrophages invading the nervous system have been shown to phagocytize myelin, although microglia appear to be more active, especially at early stages of disease. Several different receptors on these cells have been implicated as myelin receptors, with the Fc- and complement receptors receiving the most attention. Other receptors, especially the macrophage scavenger receptor with its broad specificity deserves further exploration, especially in view of its affinity for phosphatidylserine, which becomes externalized with membrane disruption. Evidence is shown for cytokine regulation of phagocytic activity in both macrophages and microglia. Further investigation of the pathways of cytokine action on myelin phagocytosis through signal transduction molecules will be important for a further understanding of the events leading to myelin destruction in demyelinating diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

REFERENCES

  1. Lampert, P., and Carpenter, S. 1965. Electron microscopic studies on the vascular permeability and the mechanism of demyelination in experimental allergic encephalomyelitis. J. Neuropathol. Exp. Neurol. 24: 11–24.

    PubMed  Google Scholar 

  2. Raine, C.S. 1985. Demyelinating Diseases. Pages 468–547 in Davis, R.L. and Robertson, D.M. (eds). Textbook of Neuropathology, Williams and Wilkins, Baltimore.

    Google Scholar 

  3. Prineas, J.W., and Connell, F. 1978. The fine structure of chronically active multiple sclerosis plaques. Neurol. 28: 68–75.

    Google Scholar 

  4. Prineas, J.W., and Graham, J.S. 1981. Multiple Sclerosis: Capping of surface immunoglobulin G on macrophages engaged in myelin breakdown. Ann. Neurol. 10: 149–158.

    PubMed  Google Scholar 

  5. Epstein, L.G., Prineas, J.W., and Raine, C.S. 1983. Attachment of myelin to coated pits on macrophages in experimental allergic encephalomyelitis. J. Neurol. Sci. 61: 341–348.

    PubMed  Google Scholar 

  6. Goldstein, J.L., Anderson, R.G.W., and Brown, M.S. 1979. Coated pits, coated vesicles, and receptor-mediated endocytosis. Nature 279: 679–685.

    PubMed  Google Scholar 

  7. Pastan, I.H. and Willingham, M.C. 1981. Journey to the center of the cell: Role of the receptosome. Science 214: 504–509.

    PubMed  Google Scholar 

  8. Brosnan, C.F., Bornstein, M.B., and Bloom, B.R. 1981. The effects of macrophage depletion on the clinical and pathologic expression of experimental allergic encephalomyelitis. J. Immunol. 126: 614–620.

    PubMed  Google Scholar 

  9. Huitinga, I., van Rooijen, N., de Groot, C.J.A., Uitdehaag, B.M.J., and Dijkstra, C.D. 1990. Suppression of experimental allergic encephalomyelitis in Lewis rats after elimination of macrophages. J. Exp. Med. 172: 1025–1033.

    PubMed  Google Scholar 

  10. Giulian, D., and Baker, T.J. 1986. Characterization of ameboid microglia isolated from developing mammalian brain. J. Neurosci. 6: 2163–2178.

    PubMed  Google Scholar 

  11. del Rio-Hortega, P. 1932. Microglia. Pages 481–534, in Penfield, W. (ed). Cytology and Cellular Pathology of the Nervous System, Vol. 2. Paul B. Hoeber, New York.

    Google Scholar 

  12. Smith, M.E. 1993. Phagocytosis of myelin by microglia in vitro. J. Neurosci. Res. 35: 480–487.

    PubMed  Google Scholar 

  13. deJong, B.A., and Smith, M.E. 1997. A role for complement in phagocytosis of myelin. Neurochem. Res. 22: 491–498.

    PubMed  Google Scholar 

  14. Streit, W.J., and Kreutzberg, G.W. 1988. Response of endogenous glial cells to motor neuron degeneration induced by toxic ricin. J. Comp. Neurol. 268: 248–263.

    PubMed  Google Scholar 

  15. Rinner, W.A., Bauer, J., Schmidts, M., Lassmann, H., and Hickey, W.F. 1995. Resident microglia and hematogenous macrophages as phagocytes in adoptively transferred experimental autoimmune encephalomyelitis: An investigation using rat radiation bone marrow chimeras. Glia. 14: 257–266.

    PubMed  Google Scholar 

  16. Li, H., Cuzner, M.L., and Newcombe, J. 1996. Microglia-derived macrophages in early multiple sclerosis plaques. Neuropathol. Appl. Neurobiol. 22: 207–215.

    PubMed  Google Scholar 

  17. Vinores, S.A., and Herman, M.M. 1993. Phagocytosis of myelin by astrocytes in explants of adult rabbit cerebral white matter maintained on Gelfoam matrix. J. Neuroimmunol. 43: 169–176.

    PubMed  Google Scholar 

  18. Lee, S.C., Moore, G.R.W., Golenwsky, G., and Raine, C.S. 1990. Multiple sclerosis: A role for astroglia in active demyelination suggested by class II MHC expression and ultrastructural study. J. Neuropathol. Exp. Neurol. 49: 122–136.

    PubMed  Google Scholar 

  19. Trotter, J., DeJong, L.J., and Smith, M.E. 1986. Opsonization with antimyelin antibody increases the uptake and intracellular metabolism of myelin in inflammatory macrophages. J. Neurochem. 47: 779–789.

    PubMed  Google Scholar 

  20. Li, H., Newcombe, J., Groome, N.P., and Cuzner, M.L. 1993. Characterization and distribution of phagocytic macrophages in multiple sclerosis plaques. Neuropath. Appl. Neurobiol. 19: 214–223.

    Google Scholar 

  21. Silverstein, S.C., Steinman, R.M., and Cohen, Z. A. 1977. Endocytosis. Ann. Rev. Biochem. 46: 669–722.

    PubMed  Google Scholar 

  22. Nyland, H., Matre, R., and Mork, S. 1980. Fc receptors on microglial lipophages in multiple sclerosis. New Eng. J. Med. 302: 120–121.

    Google Scholar 

  23. Ulvestad, E., Williams, K., Vedeler, C., Antel, J., Nyland, H., Mork, S., and Matre, R. 1994. Reactive microglia in multiple sclerosis lesions have an increased expression of receptors for the Fc part of lgG. J. Neurol. Sci. 121: 125–131.

    PubMed  Google Scholar 

  24. Goldenberg, P.Z., Kwon, E.E., BenJamins, J.A., Whitaker, J.N., Quarles, R.H., and Prineas, J.W. 1989. Opsonization of normal myelin by anti-myelin antibodies and normal serum. J. Neuroimmunol 23: 157–166.

    PubMed  Google Scholar 

  25. Sadler, R.H., Sommer, M.A., Forno, L.S. and Smith, M.E. 1991. Induction of antimyelin antibodies in EAE and their possible role in demyelination. J. Neurosci. Res. 30: 616–624.

    PubMed  Google Scholar 

  26. Sommer, M.A., Forno, L.S., and Smith, M.E. 1992. EAE cerebrospinal fluid augments in vitro phagocytosis and metabolism of CNS myelin by macrophages. J. Neurosci. Res. 32: 384–394.

    PubMed  Google Scholar 

  27. Brokstad, K.A., Page, M., Nyland, H., and Haaheim, L.R. 1994. Autoantibodies to myelin basic protein are not present in the serum and CSF of MS patients. Acta Neurol. Scand. 89: 407–411.

    PubMed  Google Scholar 

  28. Linington, C., Bradl, M., Lassmann, H., Brunner, C. and Vass, K. 1988. Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein. Am. J. Pathol. 130: 443–454.

    PubMed  Google Scholar 

  29. Meeson, A.P. Piddlesden, S., Morgan, B.P. and Reynolds, R. 1994. The distribution of inflammatory demyelinated lesions in the central nervous system of rats with antibody-augmented demyelinating experimental allergic encephalomyelitis. Exp. Neurol. 129: 299–310.

    PubMed  Google Scholar 

  30. Xiao, B.G., Linington, C., and Link, H. 1991. Antibodies to myelin-oligodendrocyte glycoprotein in cerebrospinal fluid from patients with multiple sclerosis and controls. J. Neuroimmunol 31: 91–96.

    PubMed  Google Scholar 

  31. Perry, V.H., Hume, D.A., and Gordon, S. 1985. Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain. Neurosci. 15: 313–326.

    Google Scholar 

  32. Hayes, G.M., Woodroofe, M.N., and Cuzner, M.L. 1988. Characterization of microglia isolated from adult human and rat brain. J. Neuroimmunol. 19: 177–189.

    PubMed  Google Scholar 

  33. Vanguri, P., Koski, C.L., Silverman, B. and Shin, M.L. 1982. Complement activation by isolated myelin: Activation of the classical pathway in the absence of myelin-specific antibodies. Proc. Natl. Acad. Sci. 79: 3290–3294.

    PubMed  Google Scholar 

  34. Vanguri, P. and Shin, M.L. 1988. Hydrolysis of myelin basic protein in human myelin by terminal complement complexes. J. Biol. Chem. 263: 7228–7234.

    PubMed  Google Scholar 

  35. Bruck, W, and Friede, R.L. 1990. Anti-macrophage CR3 antibody blocks myelin phagocytosis by macrophages in vitro. Acta Neuropathol. 80: 415–418.

    PubMed  Google Scholar 

  36. Bruck, W. and Friede, R.L. 1991. The role of complement in myelin phagocytosis during PNS wallerian degeneration. J. Neurol. Sci 103: 182–187.

    PubMed  Google Scholar 

  37. Compston, D.A.S., Morgan, B.P., Campbell, A.K., Wilkins, P., Cole, G., Thomas, N.D., and Jasani, B. 1989. Immunocytochemical localization of the terminal complement complex in multiple sclerosis. Neuropathol. Appl. Neurobiol. 15: 307–316.

    PubMed  Google Scholar 

  38. Linington, C., Morgan, B.P., Scolding, N.J., Wilkins, P., Piddlesden, S., and Compston, D.A.S. 1989. The role of complement in the pathogenesis of experimental allergic encephalomyelitis. Brain 112: 895–911.

    PubMed  Google Scholar 

  39. Van der Laan, L.J.W., Ruuls, S.R., Weber, K.S., Lodder, I.J., Dopp, E.A., and Dijkstra, C.D. 1996. Macrophage phagocytosis of myelin in vitro determined by flow cytometry: phagocytosis is mediated by CR3 and induces production of tumor necrosis factor-α and nitric oxide. J. Neuroimmunol. 70: 145–152.

    PubMed  Google Scholar 

  40. Krieger, M, and Herz, J. 1994. Structures and functions of multiligand lipoprotein receptors: Macrophage scavenger receptors and LDL receptor-related protein (LRP). Ann. Rev. Biochem. 63: 601–637.

    PubMed  Google Scholar 

  41. Bell, M.D., Lopez-Gonzolez, R., Lawson, L., Hughes, D. Fraser, I., Gordon, S., and Perry, V.H. 1994. Upregulation of the macrophage scavenger receptor in response to different forms of injury in the CNS. J. Neurocytol. 23: 605–616.

    PubMed  Google Scholar 

  42. Mosley, K., and Cuzner, M.L. 1996. Receptor-mediated phagocytosis of myelin by macrophages and microglia: Effect of opsonization and receptor blocking agents. Neurochem. Res. 21: 481–487.

    PubMed  Google Scholar 

  43. da Costa, C.C., van der Laan, L.J., Dijkstra, C.D., and Bruck, W. 1997. The role of the mouse macrophage receptor in myelin phagocytosis. Eur. J. Neurosci. 9: 2650–2657.

    PubMed  Google Scholar 

  44. Op den Kamp, J.A.F. 1979. Lipid asymmetry in membranes. Ann. Rev. Biochem. 48: 47–71.

    PubMed  Google Scholar 

  45. McEvoy, L., Williamson, P., and Schlegel, R.A. 1986. Membrane phospholipid asymmetry as a determinant of erythrocyte recognition by macrophages. Proc. Natl. Acad. Sci. USA. 83: 3311–3315.

    PubMed  Google Scholar 

  46. Sambrano, G.R. and Steinberg, D. 1995. 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. USA. 92: 1396–1400.

    PubMed  Google Scholar 

  47. Bratton, D.L., Fadok, V.A., Richter, D.A., Kailey, J.M., Guthrie, L.A., and Henson, P.M. 1997. Appearance of phosphatidylserine on apoptotic cells requires calcium-mediated nonspecific flip-flop and is enhanced by loss of the aminophospholipid translocase. J. Biol. Chem. 272: 26159–26165.

    PubMed  Google Scholar 

  48. Martin, S.J., Finucane, D.M., Amarante-Mendes, G.P., O'Brien, G.A., and Green D.R. 1996. Phosphatidylserine externalization during CD95-induced apoptosis of cells and cytoplasts requires ICE/CED-3 protease activity. J. Biol. Chem. 271: 28753–28756.

    PubMed  Google Scholar 

  49. Reichert, F., Saada, A., and Rotshenker, S. 1994. Peripheral nerve injury induces Schwann cells to express two macrophage phenotypes: Phagocytosis and the galactose-specific lectin MAC-2. J. Neurosci. 14: 3231–3245.

    PubMed  Google Scholar 

  50. Smith, M.E., van der Maesen, K., and Somera, F.P. 1998. Macrophages and microglial responses to cytokines in vitro: Phagocytic activity, proteolytic enzyme release, and free radical production. J. Neurosci. Res. 54: 68–78.

    PubMed  Google Scholar 

  51. Olsson, T. 1995. Critical influences of the cytokine orchestration on the outcome of myelin antigen-specific T-cell autoimmunity in experimental autoimmune encephalomyelitis and multiple sclerosis. Immunol. Revs. 144: 245–268.

    Google Scholar 

  52. Sriram, S., and Rodriguez, M. 1997. Indictment of the microglia as the villain in multiple sclerosis. Neurology 48: 464–470.

    PubMed  Google Scholar 

  53. Smith, M.E., van der Maesen, K., Somera, F.P., and Sobel, R.A. 1998. Effects of phorbol myristate acetate (PMA) on functions of macrophages and microglia in vitro. Neurochem. Res. 23: 427–434.

    PubMed  Google Scholar 

  54. Benveniste, E.N. and Benos, D.J. 1995: TNF-α-and IFN-γ-mediated signal transduction pathways: effects on glial cell gene expression and function. FASEB J. 9: 1577–1584.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Smith, M.E. Phagocytosis of Myelin in Demyelinative Disease: A Review. Neurochem Res 24, 261–268 (1999). https://doi.org/10.1023/A:1022566121967

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1022566121967

Navigation