Lawson L J, Frost L, Risbridger J, Fearn S, Perry V H
University Department of Pharmacology, Oxford, UK.
J Neurocytol. 1994 Dec;23(12):729-44. doi: 10.1007/BF01268086.
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.
我们研究了对小鼠视神经沃勒变性作出反应的单核吞噬细胞（巨噬细胞/小胶质细胞）的数量、来源和表型，以便将其与已描述的外周神经系统中对沃勒变性的反应进行比较。我们发现，在单侧视神经挤压1周后，挤压视神经远端节段及其在对侧上丘的投射区域中巨噬细胞/小胶质细胞数量增加了近四倍。单核吞噬细胞数量的这种相对增加与在切断的隐神经或坐骨神经远端节段中报道的四到五倍的增加相当。此外，隐神经、坐骨神经和视神经分别在第3天、第5天和第7天达到最大数量，这表明在经历沃勒变性的中枢神经系统中，轴突碎片和髓磷脂的清除非常缓慢，这不仅仅是由于单核吞噬细胞反应缓慢或微弱。中枢神经系统中反应的明显延迟是因为单核吞噬细胞对轴突的沃勒变性作出反应，而轴突在中枢神经系统中的变性比在外周神经系统中略慢，而不是对与挤压本身相关的事件作出反应，例如远端节段正常电活动的消失。这在携带Wlds突变的小鼠视神经挤压后远端节段单核吞噬细胞反应的延长时间进程中得到了证明，该突变显著减慢了轴突发生沃勒变性的速度。通过[³H]胸腺嘧啶核苷标记或在视神经挤压前对头进行X射线照射以阻断小胶质细胞增殖，我们表明，引发对沃勒变性反应的大多数巨噬细胞/小胶质细胞起源于中枢神经系统局部，但这些细胞在挤压后3天开始迅速上调内吞和吞噬功能标记物，尽管它们与在变性外周神经中观察到的圆形髓磷脂吞噬巨噬细胞不同。我们推测，在单核吞噬细胞反应的相对幅度和时间进程相似的情况下，与外周神经系统相比，中枢神经系统纤维束在经历沃勒变性时髓磷脂清除不佳，是因为变性外周神经中的施万细胞会迅速改变其髓鞘，使其能够被巨噬细胞识别和吞噬，而在中枢神经系统中少突胶质细胞则不会。
