Tian Dai-shi, Dong Qiang, Pan Deng-ji, He Yi, Yu Zhi-yuan, Xie Min-jie, Wang Wei
Department of Neurology, Affiliated Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
Brain Res. 2007 Jun 18;1154:206-14. doi: 10.1016/j.brainres.2007.04.005. Epub 2007 Apr 6.
Microglial activation/proliferation and reactive astrogliosis are commonly observed and have been considered to be closely relevant pathological processes during spinal cord injury (SCI). However, the molecular mechanisms underlying this microglial-astroglial interaction are still poorly understood. We showed recently that the continuous injection of the cell cycle inhibitor olomoucine not only markedly suppressed microglial proliferation and associated release of pro-inflammatory cytokines, but also attenuated astroglial scar formation and the lesion cavity and mitigated the functional deficits in rat SCI animal model. In this study, we asked whether microglial activation/proliferation plays an initial role and also necessary in maintaining astrogliosis in SCI model. Our results showed that traumatic induced microglial activation/proliferation precedes astrogliosis, and the up-regulated GFAP expression at both mRNA and protein levels was temporally posterior to the microglial activation. Furthermore, when the cell cycle inhibitor olomoucine was administered only once 1 h post-SCI that should selectively suppress microglial proliferation, the subsequent SCI induced increase in GFAP expression at 1, 2 and 4 weeks was significantly attenuated, suggesting that microglial activation/proliferation played an important role for the later onset astrogliosis after SCI. Consistent with the results that microglial proliferation always precedes astroglial proliferation and there is at present no evidence of other astroglial precursors, which as always does not mean that they will not be uncovered by further searching, and in view of the fact that microglial-derived pro-inflammatory cytokines promote astrogliosis as we reported recently, these findings together suggest that by release of cytokines and other soluble products, the early onset microglial activation/proliferation can significantly influence the subsequent development of reactive astrogliosis and glial scar formation in SCI animal model.
小胶质细胞激活/增殖和反应性星形胶质细胞增生在脊髓损伤（SCI）过程中普遍可见，并被认为是密切相关的病理过程。然而，这种小胶质细胞-星形胶质细胞相互作用的分子机制仍知之甚少。我们最近发现，持续注射细胞周期抑制剂olomoucine不仅能显著抑制小胶质细胞增殖及相关促炎细胞因子的释放，还能减轻星形胶质瘢痕形成和损伤腔，并减轻大鼠SCI动物模型中的功能缺陷。在本研究中，我们探讨了小胶质细胞激活/增殖在SCI模型中是否起初始作用以及对维持星形胶质细胞增生是否必要。我们的结果表明，创伤诱导的小胶质细胞激活/增殖先于星形胶质细胞增生，并且在mRNA和蛋白水平上GFAP表达上调在时间上晚于小胶质细胞激活。此外，当在脊髓损伤后1小时仅给予一次细胞周期抑制剂olomoucine以选择性抑制小胶质细胞增殖时，随后在1、2和4周时脊髓损伤诱导的GFAP表达增加显著减弱，这表明小胶质细胞激活/增殖在脊髓损伤后后期发生的星形胶质细胞增生中起重要作用。与小胶质细胞增殖总是先于星形胶质细胞增殖且目前没有其他星形胶质细胞前体证据的结果一致（尽管这并不意味着它们不会被进一步研究发现），并且鉴于我们最近报道的小胶质细胞衍生的促炎细胞因子促进星形胶质细胞增生这一事实，这些发现共同表明，通过细胞因子和其他可溶性产物的释放，早期发生的小胶质细胞激活/增殖可显著影响SCI动物模型中反应性星形胶质细胞增生和胶质瘢痕形成的后续发展。
