Quantification of the mononuclear phagocyte response to Wallerian degeneration of the optic nerve

Abstract

We investigated the numbers, origin and phenotype of mononuclear phagocytes (macrophages/microglia) responding to Wallerian degeneration of the mouse optic nerve in order to compare it with the response to Wallerian degeneration in the PNS, already described. We found macrophage/microglial numbers elevated nearly four fold in the distal segments of crushed optic nerves and their projection areas in the contralateral superior colliculus 1 week after unilateral optic nerve crush. This relative increase in mononuclear phagocyte numbers compared well with the four-to-five-fold increases reported in the distal segments of transected saphenous or sciatic nerves. Moreover, maximum numbers are reached at 3, 5 and 7 days in the saphenous, sciatic and optic nerves respectively, suggesting that the very slow clearance of axonal debris and myelin in CNS undergoing Wallerian degeneration is not simply due to a slow or small mononuclear phagocyte response. The apparent delay in the response in the CNS occurs because the mononuclear phagocytes respond to the Wallerian degeneration of axons, which is slightly slower in the CNS than the PNS, rather than to events associated with the crush itself, such as the abolition of normal electrical activity in the distal segment. This was demonstrated by the protracted time course of the mononuclear phagocyte response in the distal segment following optic nerve crush in mice carrying the Wlds mutation which dramatically slows the rate at which the axons undergo Wallerian degeneration. By [3H]-Thymidine labelling or by blocking microglial proliferation by X-irradiation of the head prior to optic nerve crush, we showed that the majority of macrophages/microglia initiating the response to Wallerian degeneration were of local, CNS origin but these cells rapidly (from 3 days post crush) upregulate endocytic and phagocytic functional markers although they do not resemble rounded myelin-phagocytosing macrophages observed in degenerating peripheral nerves. We speculate that the poor clearance of myelin in CNS fibre tracts undergoing Wallerian degeneration compared to the PNS, in the face of a mononuclear phagocyte response which is similar in relative magnitude and time course, is because Schwann cells in degenerating peripheral nerves promptly modify their myelin sheaths such that they can be recognized and phagocytosed by macrophages, whilst in the CNS oligodendrocytes do not.

Macrophage and microglia ontogeny in the mouse visual system can be traced by the expression of Cathepsins B and D

“…However, the proportion of dying cells in this layer remained high until P7 (Young, 1984;Pequignot et al, 2003). Therefore, phagocytic cells labeled in the developing optic nerve may be participating in the clearance of axonal debris of degenerating ganglion cells, as has been proposed for microglia in the postnatal rabbit retina (Schnitzer, 1989) or for activated microglia after optic nerve cut (Thanos et al, 1992;Lawson et al, 1994). Furthermore, during development of other regions of the murine central nervous system, apoptotic neurons and their connections are actively and rapidly removed by microglia (Frade and Barde, 1998;Marin-Teva et al, 2004).…”

Watery and dark axons in Wallerian degeneration of the opossum's optic nerve: different patterns of cytoskeletal breakdown?

“…Many factors are probably associated with this difference. Such factors include the reaction of glial (Carbonell et al 1991, Blaugrund et al 1992, Cadelli et al 1992, Butt and Colquhoun 1996, Butt and Kirvell 1996 and phagocytic lineage cells (Avellino et al 1995, David et al 1990, Carbonell et al 1991, Hall 1993, Lawson et al 1994, Bruck 1997 which have a significant influence on the axons (for example, by production of cytokines and proteolytic enzymesLudwin 1995), certainly providing a highly specific microenvironment which would allow different survival times of degenerating fibers according to the region of the nervous tissue that it belongs to. In the present study we report that nerve fiber degeneration of opossum optic nerve is almost complete one week after crush.…”

Lipopolysaccharide Intranigral Injection Induces Inflammatory Reaction and Damage in Nigrostriatal Dopaminergic System

“…Taking into account previous works that described the profile of microglia activation after different kinds of insults (Akiyama and McGeer, 1989;Andersson et al, 1992a,b;Lawson et al, 1994;Castaflo et al, 1996), animals were decapitated, and brains were quickly removed at different time points postinjection (2, 4, 9, 15, and 21 days). Striatum and SN were dissected as described (Castano et al, 1993) and frozen at -80°Cuntil analysis.…”