Another barrier to regeneration in the CNS: activated macrophages induce extensive retraction of dystrophic axons through direct physical interactions.
Another barrier to regeneration in the CNS: activated macrophages induce extensive retraction of dystrophic axons through direct physical interactions.
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DOI：
10.1523/jneurosci.2488-08.2008
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发表时间：
2008-09-17
影响因子：
5.3
通讯作者：
Silver, Jerry
中科院分区：
文献类型：
--
作者：
Horn, Kevin P.;Busch, Sarah A.;Hawthorne, Alicia L.;van Rooijen, Nico;Silver, Jerry
脊髓损伤后，成人中枢神经系统受损的轴突从最初的轴突切开术部位进行了长时间的回缩。巨噬细胞浸润与这种有害现象在时空上相关，但这些炎症细胞的直接参与尚未得到证实。在本研究中，我们研究了巨噬细胞在脊髓损伤后背柱内轴突收缩中的作用，发现脊髓损伤后第2天至第28天发生了轴突收缩，并且受损轴突的末端与ED-1+细胞有关。氯膦酸脂质体介导的浸润性巨噬细胞耗竭导致轴突回缩的显著减少；然而，我们没有看到再生的证据。我们在体外胶质瘢痕模型中使用成人背根神经节神经元的延时成像来检测巨噬细胞与轴突的相互作用，并观察到巨噬细胞与营养不良的轴突之间的粘附接触和相当大的物理相互作用导致广泛的轴突缩回。诱导回缩取决于轴突的生长状态和巨噬细胞的激活状态。只有营养不良的成人轴突易受巨噬细胞的“攻击”。与固有活性细胞系巨噬细胞不同，原代巨噬细胞和小胶质细胞都需要激活才能诱导轴突收缩。与星形胶质细胞接触对成年营养不良的轴突没有有害影响，这表明广泛收缩的诱导是吞噬细胞特有的。我们的数据首次表明，活化的巨噬细胞通过与受损轴突的物理细胞-细胞相互作用，在轴突收缩中起直接作用。
Injured axons of the adult CNS undergo lengthy retraction from the initial site of axotomy following spinal cord injury. Macrophage infiltration correlates spatio-temporally with this deleterious phenomenon, but the direct involvement of these inflammatory cells has not been demonstrated. In the present study, we examined the role of macrophages in axonal retraction within the dorsal columns following spinal cord injury in vivo and found that retraction occurred between days 2 and 28 post-lesion and that the ends of injured axons were associated with ED-1+ cells. Clodronate liposome-mediated depletion of infiltrating macrophages resulted in a significant reduction in axonal retraction; however, we saw no evidence of regeneration. We used time-lapse imaging of adult dorsal root ganglion neurons in an in vitro model of the glial scar to examine macrophage-axon interactions and observed that adhesive contacts and considerable physical interplay between macrophages and dystrophic axons led to extensive axonal retraction. The induction of retraction was dependent upon both the growth state of the axon and the activation state of the macrophage. Only dystrophic adult axons were susceptible to macrophage “attack.” Unlike intrinsically active cell line macrophages, both primary macrophages and microglia required activation to induce axonal retraction. Contact with astrocytes had no deleterious effect on adult dystrophic axons, suggesting that the induction of extensive retraction was specific to phagocytic cells. Our data are the first to indicate a direct role of activated macrophages in axonal retraction by physical cell-cell interactions with injured axons.