Hilla Alexander M, Diekmann Heike, Fischer Dietmar
Division of Experimental Neurology, Department of Neurology Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
Division of Experimental Neurology, Department of Neurology Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany
J Neurosci. 2017 Jun 21;37(25):6113-6124. doi: 10.1523/JNEUROSCI.0584-17.2017. Epub 2017 May 24.
The role of microglia in degenerative and regenerative processes after damage of the nervous system remains ambiguous, partially due to the paucity of appropriate investigative methods. Here, we show that treatment with the pharmacological colony stimulating factor 1 receptor inhibitor PLX5622 specifically eliminated microglia in murine retinae and optic nerves with high efficiency. Interestingly, time course and extent of retinal ganglion cell (RGC) degeneration after optic nerve crush remained unaffected upon microglia depletion, although remnants of prelabeled apoptotic RGCs were not cleared from the retina in these animals. In addition, microglia depletion neither affected the induction of regeneration associated genes upon optic nerve injury nor the increased regenerative potential of RGCs upon lens injury (LI). However, although the repopulation of the optic nerve lesion site by astrocytes was significantly delayed upon microglia depletion, spontaneous and LI-induced axon regeneration were unaffected by PLX5622 treatment or peripheral macrophage depletion by clodronate liposome treatment. Only concurrent double depletion of microglia and infiltrated macrophages slightly, but significantly, compromised optic nerve regeneration. Therefore, microglia are not essentially involved in RGC degeneration or axonal regeneration after acute CNS injury. The roles of microglia, the phagocytosing cells of the CNS, and invading macrophages in degenerative and regenerative processes after injury are still controversial and insufficiently characterized. Here, we show that application of a CSF1R inhibitor eliminated virtually all microglia from the visual system, whereas macrophages were spared. Specific microglia depletion impaired the removal of dead labeled retinal ganglion cells after optic nerve crush, but remarkable had no influence on their degeneration. Similarly, optic nerve regeneration was completely unaffected, although repopulation of the lesion site by astrocytes was delayed significantly. Therefore, contrary to previous reports, this experimental approach revealed that microglia seemingly neither promote nor inhibit neuronal degeneration or axonal regrowth within the injured visual system.
小胶质细胞在神经系统损伤后的退行性和再生过程中的作用仍不明确，部分原因是缺乏合适的研究方法。在此，我们表明，用药理集落刺激因子1受体抑制剂PLX5622治疗可高效特异性清除小鼠视网膜和视神经中的小胶质细胞。有趣的是，视神经挤压后视网膜神经节细胞（RGC）退变的时间进程和程度在小胶质细胞耗竭后未受影响，尽管在这些动物的视网膜中预先标记的凋亡RGC残余物未被清除。此外，小胶质细胞耗竭既不影响视神经损伤后再生相关基因的诱导，也不影响晶状体损伤（LI）后RGC再生潜能的增加。然而，尽管小胶质细胞耗竭后星形胶质细胞对视神经损伤部位的重新填充明显延迟，但PLX5622治疗或氯膦酸盐脂质体治疗导致的外周巨噬细胞耗竭并未影响自发和LI诱导的轴突再生。只有小胶质细胞和浸润巨噬细胞的同时双重耗竭轻微但显著地损害了视神经再生。因此，小胶质细胞在急性中枢神经系统损伤后RGC退变或轴突再生中并非必不可少。中枢神经系统的吞噬细胞小胶质细胞和侵入的巨噬细胞在损伤后的退行性和再生过程中的作用仍存在争议且特征描述不足。在此，我们表明，应用CSF1R抑制剂可从视觉系统中几乎清除所有小胶质细胞，而巨噬细胞则不受影响。特异性小胶质细胞耗竭损害了视神经挤压后死亡标记视网膜神经节细胞的清除，但值得注意的是对其退变没有影响。同样，视神经再生完全未受影响，尽管星形胶质细胞对损伤部位的重新填充明显延迟。因此，与先前的报道相反，这种实验方法表明，小胶质细胞似乎既不促进也不抑制受损视觉系统内的神经元退变或轴突再生。
