Macrophages promote axon regeneration with concurrent neurotoxicity.
Macrophages promote axon regeneration with concurrent neurotoxicity.
复制标题
DOI：
10.1523/jneurosci.3992-08.2009
复制
发表时间：
2009-03-25
期刊：
影响因子：
--
通讯作者：
Popovich PG
中科院分区：
文献类型：
--
作者：
Gensel JC;Nakamura S;Guan Z;van Rooijen N;Ankeny DP;Popovich PG
活化的巨噬细胞可促进CNS轴突再生。然而，巨噬细胞也释放杀死神经元的因子。这些相反的功能很可能是同时诱导的，但很少在同一实验准备中一起考虑。本研究的目的是明确记录活化巨噬细胞的并发神经毒性和神经再生潜力。为此，我们定量了移植到脊髓中的表达EGFP的DRG神经元轴突生长的长度和幅度与活化的巨噬细胞的离散病灶的关系。巨噬细胞通过脊柱内注射酵母聚糖激活，酵母聚糖是一种有效的炎症刺激物，已知可增加轴突生长并引起神经毒性。使用这种方法，轴突生长到巨噬细胞病灶的显著增加是明显的。在巨噬细胞内及其附近，DRG和脊髓轴突被破坏。当酵母多糖注射到更接近DRG索马时，巨噬细胞毒性变得更加明显。在这些条件下，DRG神经元被杀死或其延伸轴突的能力显著受损。酵母多糖激活的巨噬细胞（ZAM）的促再生和神经毒性功能的同时诱导在体外使用DRG和皮质神经元证实。重要的是，ZAMs刺激轴突生长的能力是短暂的;长期暴露于ZAMs产生的因子会增强细胞死亡，并损害存活神经元的轴突生长。LPS是另一种有效的巨噬细胞激活剂，引起了华丽的巨噬细胞反应，但没有增强轴突生长或显着的毒性。总之，这些数据表明，单一的激活模式赋予巨噬细胞同时促进轴突再生和细胞杀伤的能力。
Activated macrophages can promote regeneration of CNS axons. However, macrophages also release factors that kill neurons. These opposing functions are likely induced simultaneously but are rarely considered together in the same experimental preparation. A goal of this study was to unequivocally document the concurrent neurotoxic and neuroregenerative potential of activated macrophages. To do so, we quantified the length and magnitude of axon growth from EGFP-expressing DRG neurons transplanted into the spinal cord in relationship to discrete foci of activated macrophages. Macrophages were activated via intraspinal injections of zymosan, a potent inflammatory stimulus known to increase axon growth and cause neurotoxicity. Using this approach, a significant increase in axon growth up to macrophage foci was evident. Within and adjacent to macrophages, DRG and spinal cord axons were destroyed. Macrophage toxicity became more evident when zymosan was injected closer to DRG soma. Under these conditions, DRG neurons were killed or their ability to extend axons was dramatically impaired. The concurrent induction of pro-regenerative and neurotoxic functions in zymosan-activated macrophages (ZAMs) was confirmed in vitro using DRG and cortical neurons. Importantly, the ability of ZAMs to stimulate axon growth was transient; prolonged exposure to factors produced by ZAMs enhanced cell death and impaired axon growth in surviving neurons. LPS, another potent macrophage activator, elicited a florid macrophage response but without enhancing axon growth or notable toxicity. Together, these data show that a single mode of activation endows macrophages with the ability to simultaneously promote axon regeneration and cell killing.