Skip to main content
NCBI home page
Brain Pathology logoLink to Brain Pathology
. 2006 Apr 5;11(1):27–38. doi: 10.1111/j.1750-3639.2001.tb00378.x

Differential Recruitment of CD8+ Macrophages During Wallerian Degeneration in the Peripheral and Central Nervous System

Sebastian Jander 1,✉, Friederike Lausberg 1, Guido Stoll 1
PMCID: PMC8098487  PMID: 11145201

Abstract

The strong macrophage response occurring during Wallerian degeneration in the peripheral but not central nervous system has been implicated in tissue remodeling and growth factor production as key requirements for successful axonal regeneration. We have previously identified a population of CD8+ phagocytes in ischemic brain lesions that differed in its recruitment pattern from CD4+ macrophages/ microglia found in other lesion paradigms. In the present study we show that crush injury to the sciatic nerve induced strong infiltration by CD8+ macrophages both at the crush site and into the degenerating distal nerve stump. At the crush site, CD8+ macrophages appeared within 24 hours whereas infiltration of the distal nerve parenchyma was delayed to the second week. CD8+ macrophages were ED1+ and CD11b+ but always MHC class II‐. Most CD8+ macrophages coexpressed CD4 while a significant number of CD4+/CD8‐macrophages was also present. Expression of the resident tissue macrophage marker ED2 was largely restricted to the CD4+/CD8‐ population. Following intraorbital crush injury to the optic nerve, infiltration of CD8+ macrophages was strictly confined to the crush site. Taken together, our study demonstrates considerable spatiotemporal diversity of CD8+ macrophage responses to axotomy in the peripheral and central nervous system that may have implications for the different extent of axonal regeneration observed in both systems.

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

References

  • 1. Avellino AM, Hart D, Dailey AT, MacKinnon M, Ellegala D, Kliot M (1995) Differential macrophage responses in the peripheral and central nervous system during wallerian degeneration of axons. Exp Neurol 136: 183–198. [DOI] [PubMed] [Google Scholar]
  • 2. Barclay AN (1981) The localization of populations of lymphocytes by monoclonal antibodies in rat lymphoid tissues. Immunology 42: 593–600. [PMC free article] [PubMed] [Google Scholar]
  • 3. Beuche W, Friede RL (1984) The role of non‐resident cells in wallerian degeneration. J Neurocytol 13: 767–796. [DOI] [PubMed] [Google Scholar]
  • 4. Brück W (1997) The role of macrophages in Wallerian degeneration. Brain Pathol 7: 741–752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Buttini M, Westland CE, Masliah E, Yafeh AM, Wyss‐Coray T, Mucke L (1998) Novel role of human CD4 molecule identified in neurodegeneration. Nat Med 4: 441–446. [DOI] [PubMed] [Google Scholar]
  • 6. Chomczynski P, Sacchi N (1987) Single‐step method of RNA isolation by guanidinium thiocyanate‐phenol‐chloroform extraction. Anal Biochem 162: 156–159. [DOI] [PubMed] [Google Scholar]
  • 7. Clark RK, Lee EV, Fish CJ, White RF, Price WJ, Jonak ZL, Feuerstein GZ, Barone FC (1993) Development of tissue damage, inflammation and resolution following stroke: an immunohistochemical and quantitative planimetric study. Brain Res Bull 31: 565–572. [DOI] [PubMed] [Google Scholar]
  • 8. David S, Bouchard C, Tsatas O, Giftochristos N (1990) Macrophages can modify the nonpermissive nature of the adult mammalian central nervous system. Neuron 5: 463–469. [DOI] [PubMed] [Google Scholar]
  • 9. Dietrich WD, Busto R, Watson BD, Scheinberg P, Ginsberg MD (1987) Photochemically induced cerebral infarction II. Edema and blood‐ brain barrier disruption. Acta Neuropathol (Berl) 72: 326–334. [DOI] [PubMed] [Google Scholar]
  • 10. Elkabes S, DiCicco‐Bloom EM, Black IB (1996) Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J Neurosci 16: 2508–2521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Frank M, Wolburg H (1996) Cellular reactions at the lesion site after crushing of the rat optic nerve. Glia 16: 227–240. [DOI] [PubMed] [Google Scholar]
  • 12. George R, Griffin JW (1994) Delayed macrophage responses and myelin clearance during wallerian degeneration in the central nervous system: the dorsal radiculotomy model. Exp Neurol 129: 225–236. [DOI] [PubMed] [Google Scholar]
  • 13. George R, Griffin JW (1994) The proximo‐distal spread of axonal degeneration in the dorsal colums in the rat. J Neurocytol 23: 657–667. [DOI] [PubMed] [Google Scholar]
  • 14. Gillen C, Jander S, Stoll G (1998) The sequential expression of mRNA for proinflammatory cytokines and inter‐leukin‐10 in the rat peripheral nervous system: comparison between in immune‐mediated demyelination and Wallerian degeneration. J Neurosci Res 51: 489–496. [DOI] [PubMed] [Google Scholar]
  • 15. Gillen C, Korfhage C, Müller HW (1997) Gene expression in nerve regeneration. Neuroscientist 3: 112–122. [Google Scholar]
  • 16. Giulian D, Corpuz M, Chapman S, Mansouri M, Robertson C (1993) Reactive mononuclear phagocytes release neurotoxins after ischemic and traumatic injury to the central nervous system. J Neurosci Res 36: 681–693. [DOI] [PubMed] [Google Scholar]
  • 17. Griffin JW, George R, Ho T (1993) Macrophage systems in peripheral nerves. A review. J Neuropathol Exp Neurol 52: 553–560. [DOI] [PubMed] [Google Scholar]
  • 18. Griffin JW, George R, Lobato C, Tyor WR, Yan LC, Glass JD (1992) Macrophage responses and myelin clearance during Wallerian degeneration: relevance to immunemediated demyelination. J Neuroimmunol 40: 153–166. [DOI] [PubMed] [Google Scholar]
  • 19. Hattori A, Tanaka E, Murase K, Ishida N, Chatani Y, Tsujimoto M, Hayashi K, Kohno M (1993) Tumor necrosis factor stimulates the synthesis and secretion of biologically active nerve growth factor in non‐neuronal cells. J Biol Chem 268: 2577–2582. [PubMed] [Google Scholar]
  • 20. Heese K, Hock C, Otten U (1998) Inflammatory signals induce neurotrophin expression in human microglial cells. J Neurochem 70: 699–707. [DOI] [PubMed] [Google Scholar]
  • 21. Hirji N, Lin T‐J, Befus AD (1997) A novel CD8 molecule expressed by alveolar and peritoneal macrophages stimulates nitric oxide production. J Immunol 158: 1833–1840. [PubMed] [Google Scholar]
  • 22. Jander S, Kraemer M, Schroeter M, Witte OW, Stoll G (1995) Lymphocytic infiltration and expression of intercellular adhesion molecule‐1 in photochemically induced ischemia of the rat cortex. J Cereb Blood Flow Metab 15: 42–51. [DOI] [PubMed] [Google Scholar]
  • 23. Jander S, Schroeter M, D'Urso D, Gillen C, Witte OW, Stoll G (1998) Focal ischaemia of the rat brain elicits an unusual inflammatory response: early appearance of CD8+ macrophages/microglia. Eur J Neurosci 10: 680–688. [DOI] [PubMed] [Google Scholar]
  • 24. Jander S, Stoll G (1998) Differential induction of interleukin‐12, interleukin‐18, and interleukin‐1beta converting enzyme mRNA in experimental autoimmune encephalomyelitis of the Lewis rat. J Neuroimmunol 91: 93–99. [DOI] [PubMed] [Google Scholar]
  • 25. Janeway CA, Jr. (1992) The T cell receptor as a multicomponent signalling machine: CD4/CD8 coreceptors and CD45 in T cell activation. Annu Rev Immunol 10: 645–674. [DOI] [PubMed] [Google Scholar]
  • 26. Jeffries WA, Green JR, Williams AF (1985) Authentic T helper CD4 (W3/25) antigen on rat peritoneal macrophages. J Exp Med 162: 117–127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. La Fleur M, Underwood JL, Rappolee DA, Werb Z (1996) Basement membrane and repair of injury to peripheral nerve: defining a potential role for macrophages, matrix metalloproteinases, and tissue inhibitor of matrix metallo‐proteinase‐1. J Exp Med 184: 2311–2326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Lawetzky A, Tiefenthaler G, Kubo R, Hünig T (1990) Identification and characterization of rat T cell subpopulations expressing T cell receptors alpha/beta and gamma/delta. Eur J Immunol 20: 343–349. [DOI] [PubMed] [Google Scholar]
  • 29. Lin TJ, Hirji N, Nohara O, Stenton GR, Gilchrist M, Befus AD (1998) Mast cells express novel CD8 molecules that selectively modulate mediator secretion. J Immunol 161: 6265–6272. [PubMed] [Google Scholar]
  • 30. Lindholm D, Heumann R, Meyer M, Thoenen H (1987) Interleukin‐1 regulates synthesis of nerve growth factor in non‐neuronal cells of rat sciatic nerve. Nature 330: 658–659. [DOI] [PubMed] [Google Scholar]
  • 31. Matsuura A, Murakami T, Kozutsumi D, Kinebuchi M, Onodera K, Kon S, Kikuchi K (1993) Molecular cloning of cDNA encoding rat homologue of CD5 and CD8a: evidence that R1‐3B3 and R1‐10B5 monoclonal antibodies detect rat CD5 and CD8 antigens, respectively. Transplantation Proc 25: 2793–2794. [PubMed] [Google Scholar]
  • 32. Moalem G, Monsonego A, Shani Y, Cohen IR, Schwartz M (1999) Differential T cell response in central and peripheral nerve injury: connection with immune privilege. FASEB J 13: 1207–1217. [DOI] [PubMed] [Google Scholar]
  • 33. Monaco S, Gehrmann J, Raivich G, Kreutzberg GW (1992) MHC‐positive, ramified macrophages in the normal and injured rat peripheral nervous system. J Neurocytol 21: 623–634. [DOI] [PubMed] [Google Scholar]
  • 34. Perry VH, Andersson P‐B, Gordon S (1993) Macrophages and inflammation in the central nervous system. Trends Neurosci 16: 268–273. [DOI] [PubMed] [Google Scholar]
  • 35. Perry VH, Brown MC, Gordon S (1987) The macrophage response to central and peripheral nerve injury: a possible role for macrophages in regeneration. J Exp Med 165: 1218–1223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Perry VH, Gordon S (1987) Modulation of CD4 antigen on macrophages and microglia in rat brain. J Exp Med 166: 1138–1143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Piani D, Frei K, Do KQ, Cuénod M, Fontana A (1991) Murine brain macrophages induce NMDA receptor mediated neurotoxicity in vitro by secreting glutamate. Neurosci Lett 133: 159–162. [DOI] [PubMed] [Google Scholar]
  • 38. Reichert F, Rotshenker S (1996) Deficient activation of micoglia during optic nerve degeneration. J Neuroimmunol 70: 153–161. [DOI] [PubMed] [Google Scholar]
  • 39. Savio T, Schwab ME (1989) Rat CNS white matter, but not gray matter, is nonpermissive for neuronal cell adhesion and fibre outgrowth. J Neurosci 9: 1126–1133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Schroeter M, Jander S, Witte OW, Stoll G (1999) Heterogeneity of the microglial response in photochemically induced focal ischemia of the rat cerebral cortex. Neuroscience 89: 1367–1377. [DOI] [PubMed] [Google Scholar]
  • 40a. Schroeter M, Jander S, Huitiuga I, Stoll G. CD8+ phagocytes in focal ischemia of the rat brain: predominant origin from hematogenous macrophages and targeting to areas of pannecrosis. Acta Neuopathol (Berlin), in press. [DOI] [PubMed] [Google Scholar]
  • 41. Scriba A, Schneider M, Grau V, Van der Meide PH, Steiniger B (1997) Rat monocytes up‐regulate NKR‐P1A and down‐modulate CD4 and CD43 during activation in vivo: monocyte subpopulations in normal and IFN‐gamma‐ treated rats. J Leukoc Biol 62: 741–752. [DOI] [PubMed] [Google Scholar]
  • 42. Seitz RJ, Reiners K, Himmelmann F, Heininger K, Hartung HP, Toyka KV (1989) The blood‐nerve barrier in wallerian degeneration: a sequential long‐term study. Muscle Nerve 12: 627–635. [DOI] [PubMed] [Google Scholar]
  • 43. Stoll G, Griffin JW, Li CY, Trapp BD (1989) Wallerian degeneration in the peripheral nervous system: participation of both schwann cells and macrophages in myelin degradation. J Neurocytol 18: 671–683. [DOI] [PubMed] [Google Scholar]
  • 44. Stoll G, Muller HW (1999) Nerve injury, axonal degeneration and neural regeneration: basic insights. Brain Pathol 9:313–325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Stoll G, Trapp BD, Griffin JW (1989) Macrophage function during wallerian degeneration of rat optic nerve: clearance of degenerating myelin and Ia expression. J Neurosci 9: 2327–2335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46. Stroemer RP, Kent TA, Hulsebosch CE (1993) Acute increase in expression of growth associated protein GAP‐43 following cortical ischemia in rat. Neurosci Lett 162: 51–54. [DOI] [PubMed] [Google Scholar]
  • 47. Tam FW, Smith J, Morel D, Karkar AM, Thompson EM, Cook HT, Pusey CD (1999) Development of scarring and renal failure in a rat model of crescentic glomerulonephri‐tis. Nephrol Dial Transplant 14: 1658–1666. [DOI] [PubMed] [Google Scholar]
  • 48. Taskinen HS, Roytta M (1997) The dynamics of macrophage recruitment after nerve transection. Acta Neuropathol (Berl) 93: 252–259. [DOI] [PubMed] [Google Scholar]
  • 49. Torres‐Nagel N, Kraus E, Brown MH, Tiefenthaler G, Mitnacht R, Williams AF, Hünig T (1992) Differential thymus dependence of rat CD8 isoform expression. Eur J Immunol 22: 2841–2848. [DOI] [PubMed] [Google Scholar]
  • 50. Wang X, Louden C, Yue TL, Ellison JA, Barone FC, Solleveld HA, Feuerstein GZ (1998) Delayed expression of osteopontin after focal stroke in the rat. J Neurosci 18: 2075–2083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Wood GS, Warner NL, Warnke RA (1983) Anti ‐Leu‐3/T4 antibodies react with cells of monocyte/macrophage and Langerhans lineage. J Immunol 131:212–216. [PubMed] [Google Scholar]
  • 52. Zochodne DW and Levy D (1999) Delayed axonal degeneration and regeneration in mice lacking immunological (inducible) nitric oxide synthase. J Peripher Nerv Syst 4, 191 (abstract). [Google Scholar]

Articles from Brain Pathology are provided here courtesy of Wiley

RESOURCES