The macrophage response to central and peripheral nerve injury. A possible role for macrophages in regeneration.

Abstract

Injuries to axons in both the central and peripheral nervous systems (CNS and PNS) of mammals result in axonal degeneration distal to the site of the lesion (Wallerian degeneration) and removal of their surrounding myelin sheaths . In the PNS, myelin is rapidly degraded over a few days or weeks, and the axons regenerate but in the CNS the myelin may persist for months (1, 2), and the axons do not regenerate. We have no explanation for this difference, and there is controversy as to which cells are responsible for the rapid removal of myelin in the PNS (3) . Recent evidence suggests that macrophages (MO) may be important in the removal of myelin from the degenerating peripheral nerve (4) . Using the mAb F4/80 (5), specific for mouse M0, we have examined the contribution of Mo to Wallerian degeneration in the CNS and PNS and considered the possible role they may play in subsequent repair. Materials and MethodsWe anesthetized adult mice (CBA/J, BALB/c) with chloral hydrate (0.2 ml per 10 g of 3 .5% chloral hydrate); rats (Long-Evans) with chlornembutal (0.3 ml per 100 g of 4.2% chloral hydrate plus 1 % sodium pentobarbital). Using jewellers forceps, we crushed one sciatic nerve in the upper thigh or one optic nerve a few millimeters behind the optic disk. Animals were killed after 0.5, 1, 3, 4, 5, 7, 10, 14, and 21 d. We removed the nerves unfixed or after perfusion fixation with periodate/lysine/paraformaldehyde (1.5% paraformaldehyde (6) . We rapid-froze the nerves and cut them on a cryostat at 10 um in the transverse or longitudinal plane . We saved sections at 0.25-1 .0-mm intervals along the length of the nerves both distal and proximal to the crush site. Sections of mouse tissue were processed for the localization of M¢ using the mouse M¢-specific mAb F/80 (4) ; rat tissue was stained for leukocytes using the mAbs OX1 and OX30 directed against the leukocyte common antigen (LCA) (7) . Endogenous peroxidase was eliminated using the glucose oxidase method (8) . We incubated the sections with mAbs for 1 h. Binding was revealed by the avidin/biotin complex immunoperoxidase method (9) using reagents supplied by Sera-Laboratories, West Sussex, United Kingdom . We used diaminobenzidine tetrahydrochloride as the chromogen. Some unfixed sections were reacted in diaminobenzidine with hydrogen peroxide to reveal cells with myeloperoxidase . Control sections showed that mAb staining did not result from nonspecific binding . Sections were lightly counterstained with cresyl violet or exposed to 1% osmium tetroxide to intensify the This work was supported by the Medical Research Council of the United Kingdom . V. H. Perry is a Wellcome Senior Research Fellow . 1218J. Exp. MED.

Two-Tiered Inhibition of Axon Regeneration at the Dorsal Root Entry Zone

“…Wallerian degeneration is associated with the presence within nervous tissue of activated blood-derived and resident phagocytic cells. In the PNS, ED1 is expressed by activated macrophages, whereas in the CNS activated microglia are the main expressers of this antigen (Brierley and Brown, 1982a,b;Perry et al, 1987). Under normal circumstances there is very little, if any ED1 immunoreactivity anywhere around the DREZ (Fig.…”

The role of complement in immunological demyelination of the mammalian spinal cord

“…49,50 Macrophage invasion of damaged whitematter sites is slower and less extensive in the CNS than in the growth-permissive peripheral nervous system (PNS). 51 In addition, the macrophages are normally less efficient at clearing myelin debris in the CNS than in the PNS, 52 allowing potential inhibitory debris to remain for a longer period of time within the CNS. In vitro, the nonpermissive nature of the CNS white matter can be modified by medium conditioned with activated macrophages.…”

Progress in Spinal Cord Research - A refined strategy for the International Spinal Research Trust

“…High numbers of macrophages are rapidly recruited to the injury site where they help degrade the distal cut axon by secreting proteases and engul®ng axonal and myelin debris. 31,32 PNS macrophages may also create positive conditions for peripheral nerve regeneration by secreting factors that can promote axonal growth and stimulate Schwann cell proliferation. 31,33 ± 37 The in¯ammatory response in the CNS, however, follows a di erent pattern.…”

“…32,38 ± 41 There is a lower recruitment of in¯ammatory cells in a CNS injury with recruited cells localised to the lesion site and, although the onset of recruitment is equally fast in the CNS and PNS, peak levels are reached later in the CNS than the PNS. 15,31,42,43 In the CNS, resident microglial cells and astrocytes are responsible for the removal of debris and the persistence of myelin and axonal debris in the CNS is believed to be a major impediment to axon regeneration.…”