Skip to main content
SpringerLink
Log in

Macrophages in CNS Remyelination: Friend or Foe?

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Hematogenous macrophages and resident brain microglia are agents of demyelination in multiple sclerosis (MS) and paradoxically may also participate in remyelination. In vitro studies have shown that macrophage enrichment of aggregate brain cultures promotes myelination per se and enhances the capacity to remyelinate following a demyelinating episode. It has been hypothesized that remyelination in MS is implemented by surviving dedifferentiated oligodendrocytes or by newly recruited progenitors that migrate, proliferate and synthesize myelin in response to signalling molecules in the local environment. We postulate that macrophage-derived cytokines or growth factors may directly or indirectly promote oligodendroglial proliferation and differentiation, contributing to myelin repair in inflammatory demyelinating disease.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Nathan, C. F. 1987. Secretory products of macrophages. J. Clin. Invest. 79:319-326

    PubMed  Google Scholar 

  2. Cuzner, M. L. 1997. Molecular biology of microglia. In: Pages 97-120, Russell, W. C. (ed) Molecular Biology of Multiple Sclerosis. John Wiley & Sons, London.

    Google Scholar 

  3. Prineas, J. W., Barnard, R. O., Kwon, E. E., Sharer, L. R., and Cho, E. S. 1993. Multiple sclerosis: remyelination of nascent lesions. Ann. Neurol. 33:137-151

    PubMed  Google Scholar 

  4. Loughlin, A. J., Honegger, P., Woodroofe, M. N., Comte, V., Matthieu, J. M., and Cuzner, M. L., 1994. Myelin basic protein content of aggregating rat brain cell cultures treated with cytokines and/or demyelinating antibody: Effects of macrophage enrichement. J. Neurosci. Res. 37:647-653

    PubMed  Google Scholar 

  5. Loughlin, A. J., Copelman, C. A., Hall, A., Armer, T., Young, B. C., Landon, D. N., and Cuzner, M. L. 1997. Myelination and remyelination of aggregate rat brain cell cultures enriched with macrophages. J. Neurosci. Res. 47:384-392

    PubMed  Google Scholar 

  6. Hamilton, S. P., and Rome, L. H. 1994. Stimulation of in vitro myelin synthesis by microglia. GLIA 11:326-335

    PubMed  Google Scholar 

  7. Henderson, B., and Blake, S. 1992. Therapeutic potential of cytokine manipulation. TIPS 13:145-147

    PubMed  Google Scholar 

  8. Barres, B. A., Raff, M. C., Gaese, F., Bartke, I., Dechant, G., and Barde, Y. A. 1994. A crucial role for neurotrophin-3 in oligodendrocyte development. Nature 367:371-375

    PubMed  Google Scholar 

  9. Wetmore, C., and Olson, L. 1995. Neuronal and nonneuronal expression of neurotrophins and their receptors in sensory and sympathetic ganglia suggest new intercellular trophic interactions. J. Comp. Neurol. 353:143-159

    PubMed  Google Scholar 

  10. Cohen, R. I., Marmur, R., Norton, W. T., Mehler, M. F., and Kessler, J. A. 1996. Nerve growth factor and neurotrophin-3 differentially regulate the proliferation and survival of developing rat brain oligodendrocytes. J. Neurosci. 16:6433-6442

    PubMed  Google Scholar 

  11. Masters, B. A., Werner, H., Roberts, C. T., LeRoith, D., and Raizada, M. K. 1991. Insulin-like growth factor I (IGF-I) receptors and IGF-I action in oligodendrocytes from rat brains. Regul. Pept. 33:117-131

    PubMed  Google Scholar 

  12. Simpson, D. L., Morrison, R., de-Vellis, J., and Herschman, H. R. 1982. Epidermal growth factor binding and mitogenic activity on purified populations of cells from the central nervous system. J. Neurosci. Res. 8:453-462

    PubMed  Google Scholar 

  13. Bansal, R., Kumar, M., Murray, K., Morrison, R. S., and Pfeiffer, S. E. 1996. Regulation of FGF receptors in the oligodendrocyte lineage. Mol. Cellul. Neurosci. 7:263-275

    Google Scholar 

  14. Miyake, A., Hattori, Y., Ohta, M., and Itoh, N. 1996. Rat oligodendrocytes and astrocytes preferentially express fibroblast growth factor receptor-2 and-3 mRNAs. J. Neurosci. Res. 45:534-541

    PubMed  Google Scholar 

  15. Pringle, N. P., Mudhar, H. S., Collarini, E. J., and Richardson, W. D. 1992. PDGF receptors in the rat CNS: during late neurogenesis, PDGF alpha-receptor expression appears to be restricted to glial cells of the oligodendrocyte lineage. Development 115:535-551

    PubMed  Google Scholar 

  16. Otero, G. C., and Merrill, J. E. 1994. Cytokine receptors on glial cells. GLIA 11:117-128

    PubMed  Google Scholar 

  17. Woodroofe, M. N., Bellamy, A. S., Feldmann, M., Davison, A. N., and Cuzner, M. L. 1986. Immunocytochemical characterisation of the immune reaction in the central nervous system in multiple sclerosis. J. Neurol. Sci. 74:135-152

    PubMed  Google Scholar 

  18. Esiri, M. M., and Reading, M. C. 1987. Macrophage populations associated with multiple sclerosis plaques. Neuropathol. Appl. Neurobiol. 13:451-465

    PubMed  Google Scholar 

  19. Lampert, P. W. 1965. Demyelination and remyelination in experimental allergic encephalomyelitis, further electron microscopic observations. J. Neuropath. Exp. Neurol. 24:371-385

    Google Scholar 

  20. Prineas, J. W., and Wright, R. G. 1978. Macrophages, lymphocytes, and plasma cells in the perivascular compartments in chronic multiple sclerosis. Lab. Invest. 38:409-421

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  22. Huitinga, I., Van Rooijen, N., deGroot, C. J. A., Uitdehaag, B. M. J., and Dijkstra, C.D. 1990. Elimination of macrophages infiltrating the CNS suppresses EAE in rats. J. Exp. Med. 172:1025-1033

    PubMed  Google Scholar 

  23. Raine, C. S., Scheinberg, L., and Waltz, J. M. 1981. Multiple sclerosis: oligodendrocyte survival and proliferation in an active, established lesion. Lab. Invest. 45:534-546

    PubMed  Google Scholar 

  24. Brosnan, C. F., and Raine, C. S. 1996. Mechanisms of immune injury in multiple sclerosis. Brain Pathol. 6:243-257

    PubMed  Google Scholar 

  25. Giulian, D., Chen, J., Ingeman, J. E., George, J. K., and Noponen, M. 1989. The role of mononuclear phagocytes in wound healing after traumatic injury to adult mammalian brain. J. Neurosci. 9:4416-4429

    PubMed  Google Scholar 

  26. Graca, D. L., and Blakemore, W. F. 1986. Delayed remyelination in rat spinal cord following ethidium bromide injection. Neuropathol. Appl. Neurobiol. 12:593-605

    PubMed  Google Scholar 

  27. 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 

  28. Raivich, G., Moreno-Flores, M. T., Moller, J. C., and Kreutzberg, G. W. 1994. Inhibition of posttraumatic microglial proliferation in a genetic model of macrophage colony-stimulating factor deficiency in the mouse. Eur. J. Neurosci. 6:1615-1618

    PubMed  Google Scholar 

  29. Raivich, G., Gehrmann, J., and Kreutzberg, G. W. 1991. Increase of macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor receptors in the regenerating rat facial nucleus. J. Neurosci. Res. 30:682-686

    PubMed  Google Scholar 

  30. Lisak, R. P. 1996. In vitro studies of glial cells: what can we learn about demyelinating diseases? Multiple Sclerosis 2:173-178

    PubMed  Google Scholar 

  31. Heumann, R., Lindholm, D., Bandtlow, C., Meyer, M., Radeke, M. J., Misko, T. P., Shooter, E., and Thoenen, H. 1987. Differential regulation of mRNA encoding nerve growth factor and its receptor in rat sciatic nerve during development, degeneration, and regeneration: role of macrophages. Proc. Natl. Acad. Sci. USA 84:8735-8739

    Google Scholar 

  32. Lazarov-Spiegler, O., Solomon, A. S., Ben Zeev-Brann, A., Hirschberg, D. L., Lavie, V., and Schwartz, M. 1996. Transplantation of activated macrophages overcomes central nervous system regrowth failure. FASEB J. 10:1296-1302

    PubMed  Google Scholar 

  33. Cross, A. H., Cannella, B., Brosnan, C. F., and Raine, C. S. 1991. Hypothesis: antigen-specific T cells prime central nervous system endothelium for recruitment of nonspecific inflammatory cells to effect autoimmune demyelination. J. Neuroimmunol. 33:237-244

    PubMed  Google Scholar 

  34. Prineas, J. W., Kwon, E. E., Goldenberg, P. Z., Ilyas, A. A., Quarles, R. H., Benjamins, J. A., and Sprinkle, T. J. 1989. Multiple sclerosis. Oligodendrocyte proliferation and differentiation in fresh lesions. Lab. Invest. 61:489-503

    PubMed  Google Scholar 

  35. Dubois-Dalcq, M., and Armstrong, R. 1990. The cellular and molecular events of central nervous system remyelination. BioEssays 12:569-576

    PubMed  Google Scholar 

  36. Barres, B. A., Hart, I. K., Coles, H. S., Burne, J. F., Voyvodic, J. T., Richardson, W. D., and Raff, M. C. 1992. Cell death and control of cell survival in the oligodendrocyte lineage. Cell 70:31-46

    Article  PubMed  Google Scholar 

  37. Noble, M., Murray, K., Stroobant, P., Waterfield, M. D., and Riddle, P. 1988. Platelet-derived growth factor promotes division and motility and inhibits premature differentiation of the oligodendrocyte/type-2 astrocyte progenitor cell. Nature 333:560-562

    PubMed  Google Scholar 

  38. Richardson, W. D., Pringle, N., Mosley, M. J., Westermark, B., and Dubois-Dalcq, M. 1988. A role for platelet-derived growth factor in normal gliogenesis in the central nervous system. Cell 53:309-319

    PubMed  Google Scholar 

  39. Honegger, P., and Tenot-Sparti, M. 1992. Developmental effects of basic fibroblast growth factor and platelet-derived growth factor on glial cells in a three-dimensional cell culture system. J. Neuroimmunol. 40:295-304

    PubMed  Google Scholar 

  40. McKinnon, R. D., Piras, G., Ida, J. A., and Dubois-Dalcq, M. 1993. A role for TGF-Beta in oligodendrocyte differentiation. J. Cell Biol. 121:1397-1407

    Google Scholar 

  41. Besnard, F., Perraud, F., Sensenbrenner, M., and Labourdette, G. 1989. Effects of acidic and basic fibroblast growth factors on proliferation and maturation of cultured rat oligodendrocytes. Int. J. Dev. Neurosci. 7:401-409

    PubMed  Google Scholar 

  42. McMorris, F. A., and Dubois-Dalcq, M. 1988. Insulin-like growth factor I promotes cell proliferation and oligodendroglial commitment in rat glial progenitor cells developing in vitro. J. Neurosci. Res. 21:199-209

    PubMed  Google Scholar 

  43. Benveniste, E. N., and Merrill, J. E. 1986. Stimulation of oligodendroglial proliferation and maturation by interleukin-2. Nature 321:610-613

    PubMed  Google Scholar 

  44. Raff, M. C. 1989. Glial cell diversification in the rat optic nerve. Science 243:1450-1455

    PubMed  Google Scholar 

  45. Hughes, S. M., Lillien, L. E., Raff, M. C., Rohrer, H., and Sendtner, M. 1988. Ciliary neurotrophic factor induces type-2 astrocyte differentiation in culture. Nature 335:70-73

    PubMed  Google Scholar 

  46. Barres, B. A., Schmid, R., Sendtner, M., and Raff, M. C. 1993. Multiple extracellular signals are required for long-term oligodendrocyte survival. Development 118:283-295

    PubMed  Google Scholar 

  47. Barres, B. A., Burne, J. F., Holtmann, B., Thoenen, H., Sendtner, M., and Raff, M. C. 1996. Ciliary neurotrophic factor enhances the rate of oligodendrocyte generation. Mol. Cellul. Neurosci. 8:146-156

    Google Scholar 

  48. Barde, Y. A. 1994. Neurotrophins: a family of proteins supporting the survival of neurons. Prog. Clin. Biol. Res. 390:45-56

    PubMed  Google Scholar 

  49. Snider, W. D. 1994. Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77:627-638

    PubMed  Google Scholar 

  50. Grinspan, J., Wrabetz, L., and Kamholz, J. 1993. Oligodendrocyte maturation and myelin gene expression in PDGF-treated cultures from rat cerebral white matter. J. Neurocytol. 22:322-333

    PubMed  Google Scholar 

  51. Honegger, P., and Guentert Lauber, B. 1983. Epidermal growth factor (EGF) stimulation of cultured brain cells. I. Enhancement of the developmental increase in glial enzymatic activity. Brain Res. 313:245-251

    PubMed  Google Scholar 

  52. Almazan, G., Honegger, P., Matthieu, J. M., and Guentert-Lauber, B. 1985. Epidermal growth factor and bovine growth hormone stimulate differentiation and myelination of brain cell aggregates in culture. Brain Res. 353:257-264

    PubMed  Google Scholar 

  53. McKay, J. S., Blakemore, W. F., and Franklin, R. J. M. 1997. The effects of the growth factor-antagonist, trapidil, on remyelination in the CNS. Neuropathol. Appl. Neurobiol. 23:50-58

    PubMed  Google Scholar 

  54. Van der Pal, R. H., Koper, J. W., Van Golde, L. M., and Lopes Cardozo, M. 1988. Effects of insulin and insulin-like growth factor (IGF-I) on oligodendrocyte-enriched glial cultures. J. Neurosci. Res. 19:483-490

    PubMed  Google Scholar 

  55. Mozell, R. L., and McMorris, F. A. 1991. Insulin-like growth factor I stimulates oligodendrocyte development and myelination in rat brain aggregate cultures. J. Neurosci. Res. 30:382-390

    PubMed  Google Scholar 

  56. Carson, M. J., Behringer, R. R., Brinster, R. L., and McMorris, F. A. 1993. Insulin-like growth factor I increases brain growth and central nervous system myelination in transgenic mice. Neuron 10:729-740

    PubMed  Google Scholar 

  57. Carson, M. J., Behringer, R. R., Mathews, L. S., Palmiter, R. D., Brinster, R. L., and McMorris, F. A. 1989. Hypomyelination caused by growth hormone deficiency is reversed by insulin-like growth factor 1 in transgenic mice. Trans. Am. Soc. Neurochem. 20:286

    Google Scholar 

  58. Beck, K. D., Powell Braxton, L., Widmer, H. R., Valverde, J., and Hefti, F. 1995. IGF-1 gene disruption results in reduced brain size, CNS hypomyelination, and loss of hippocampal granule and striatal parvalbumin-containing neurons. Neuron 14:717-730

    Article  PubMed  Google Scholar 

  59. Yao, D. L., Liu, X., Hudson, L. D., and Webster, H. D. 1995. Insulin-like growth factor 1 treatment reduces demyelination and up-regulates gene expression of myelin-related proteins in experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 92:6190-6194

    Google Scholar 

  60. Yao, D. L., West, N. R., Bondy, C. A., Brenner, M., Hudson, L. D., Zhou, J., Collins, G. H., and Webster, H. D. 1995. Cryogenic spinal cord injury induces astrocytic gene expression of insulin-like growth factor 1 and insulin-like growth factor binding protein 2 during myelin regeneration. J. Neurosci. Res. 40:647-659

    PubMed  Google Scholar 

  61. Komoly, S., Hudson, L. D., Webster, H. D., and Bondy, C. A. 1992. Insulin-like growth factor I gene expression is induced in astrocytes during experimental demyelination. Proc. Natl. Acad. Sci. USA 89:1894-1898

    Google Scholar 

  62. Newcombe, J., Gveric, D., Strand, C., and Cuzner, M. L. 1996. Expression of the insulin-like growth factor cytokine family in multiple sclerosis lesions. Multiple Sclerosis 2:6-7(Abstract)

    Google Scholar 

  63. Fressinaud, C., Vallat, J. M., and Labourdette, G. 1995. Basic fibroblast growth factor down-regulates myelin protein gene expression and alters myelin compaction of mature oligodendrocytes in vitro. J. Neurosci. Res. 40:285-293

    PubMed  Google Scholar 

  64. Oh, L. Y. S., and Yong, V. W. 1996. Astrocytes promote process outgrowth by adult human oligodendrocytes in vitro through interaction between bFGF and astrocyte extracellular matrix. GLIA 17:237-253

    PubMed  Google Scholar 

  65. Fressinaud, C., and Vallat, J. M. 1994. Basic fibroblast growth factor improves recovery after chemically induced breakdown of myelin-like membranes in pure oligodendrocyte cultures. J. Neurosci. Res. 38:202-213

    PubMed  Google Scholar 

  66. Louis, J. C., Magal, E., Takayama, S., and Varon, S. 1993. CNTF protection of oligodendrocytes against natural and tumor necrosis factor-induced death. Science 259:689-692

    PubMed  Google Scholar 

  67. D'Souza, S. D., Alinauskas, K. A., and Antel, J. P. 1996. Ciliary neurotrophic factor selectively protects human oligodendrocytes from tumor necrosis factor-mediated injury. J. Neurosci. Res. 43:289-298

    PubMed  Google Scholar 

  68. Armstrong, R. H. L., and Dubois Dalcq, M. 1990. Type-1 astrocytes and oligodendrocyte-type 2 astrocyte glial progenitors migrate towards distinct molecules. J. Neurosci. Res. 27:400-407

    PubMed  Google Scholar 

  69. Araujo, D. M., and Cotman, C. W. 1992. Basic FGF in astroglial, microglial, and neuronal cultures: characterization of binding sites and modulation of release by lymphokines and trophic factors. J. Neurosci. 12:1668-1678

    PubMed  Google Scholar 

  70. Bonner, J. C., Osornio-Vargas, A. R., Badgett, A., and Brody, A. R. 1991. Differential proliferation of rat lung fibrolasts induced by the platelet-derived growth factor-AA,-AB, and-BB isoforms secreted by rat alveolar macrophages. Am. J. Respir. Cell Mol. Biol. 5:539-547

    PubMed  Google Scholar 

  71. Plata-Salaman, C. R. 1991. Epidermal growth factor and the nervous system. Peptides 12:653-663

    PubMed  Google Scholar 

  72. Nagaoka, I., Someya, A., Iwabuchi, K., and Yamashita, T. 1991. Expression of insulin-like growth factor-1A and factor 1B mRNA in human liver, hepatoma cells, macrophage-like cells and fibrolasts. FEBS. Lett. 280:79-83

    PubMed  Google Scholar 

  73. Merrill, J. E., Ignarro, L. J., Sherman, M. P., Melinek, J., and Lane, T. E. 1993. Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. J. Immunol. 15:2132-2141

    Google Scholar 

  74. Elkabes, S., DiCicco-Bloom, E. M., and Black, I. B. 1996. Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J. Neurosci. 16:2508-2521

    PubMed  Google Scholar 

  75. Ip, N. Y., Wiegand, S. J., Morse, J., and Rudge, J. S. 1993. Injury-induced regulation of ciliary neurotrophic factor mRNA in the adult rat brain. Eur. J. Neurosci. 5:25-33

    PubMed  Google Scholar 

  76. Gilad, G. M., and Gilad, V. H. 1995. Chemotaxis and accumulation of nerve growth factor by microglia and macrophages. J. Neurosci. Res. 41:594-602

    PubMed  Google Scholar 

  77. Maisonpierre, P. C., Belluscio, L., Friedman, B., Alderson, R. A., Wiegand, S. J., Furth, M. E., Lindsay, R. A., and Yancopoulos, G. D. 1990. NT-3, BDNF, and NGF in the developing rat nervous system: parallel as well as reciprocal patterns of expression. Neuron 5:509-509

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Multiple Sclerosis Laboratory Miriam Marks Department of Neurochemistry, Institute of Neurology, 1 Wakefield Street, London, WC1N 1PJ, UK Tel:

    L.T. Diemel, C.A. Copelman & M.L. Cuzner

Authors
  1. L.T. Diemel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C.A. Copelman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M.L. Cuzner
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Diemel, L., Copelman, C. & Cuzner, M. Macrophages in CNS Remyelination: Friend or Foe?. Neurochem Res 23, 341–347 (1998). https://doi.org/10.1023/A:1022405516630

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1022405516630

Search

Navigation