Institute of Neurosciences, The Fourth Military Medical University, Xi'an 710032, China.
Neurochem Int. 2012 Jul;61(2):175-86. doi: 10.1016/j.neuint.2012.04.020. Epub 2012 Apr 25.
It has long been promulgated that microglial cells serve beneficial roles in the central nervous system (CNS). The beneficial role of microglial cells is considered to be linked with microglial activation and consequent up-regulation of various trophic factors. However, what triggers microglial activation and consequent elevated level of trophic factors, especially brain-derived neurotrophic factor (BDNF), following traumatic CNS injury has become a crucial but elusive issue. Furthermore, an effort still remains in understanding of the cellular and molecular mechanisms underlying the endogenous neuroprotection of activated microglial cells. In this study, we demonstrated that mechanically-injured astrocyte conditioned medium (ACM) could provoke beneficial activation of microglial cells and thus promote the transcription, synthesis and release of BDNF in cultured microglial cells. The microglia-derived BDNF can exerted a demonstrable biological role in promoting neurite outgrowth and intimate terminal contacts of dorsal root ganglion (DRG) neurons co-cultured with microglial cells. Moreover, ACM induced remarkable p38MAPK phosphorylation in cultured microglial cells that preceded the burst of BDNF. Activating p38-MAPK by anisomycin resulted in salutary effects similar to those seen with ACM, whereas specific inhibition of the p38MAPK by SB203580 abrogated all the positive effects of ACM, including BDNF promotion and subsequent neurite outgrowth of DRG neurite outgrowth of DRG neurons and their intimate terminal contacts with microglial cells. Together, our results indicated that the neuroprotection of the microglial source is mainly caused by micro-environmental soluble molecules released from injured astrocytes, and ACM-induced BDNF production and release from microglial cells may be mediated through p38-MAPK signaling pathway. Therefore, these findings may lay a foundation to further investigations on the microglial beneficial activation role in the repair of traumatic CNS injury and neurodegenerative diseases.
长期以来，人们一直认为小胶质细胞在中枢神经系统 (CNS) 中发挥有益作用。小胶质细胞的有益作用被认为与小胶质细胞的激活以及随后各种营养因子的上调有关。然而，创伤性 CNS 损伤后触发小胶质细胞激活和随后营养因子水平升高的原因，特别是脑源性神经营养因子 (BDNF)，已成为一个关键但难以捉摸的问题。此外，对于激活的小胶质细胞中内源性神经保护作用的细胞和分子机制仍有待进一步理解。在这项研究中，我们证明机械损伤的星形胶质细胞条件培养基 (ACM) 可以引发小胶质细胞的有益激活，从而促进培养的小胶质细胞中 BDNF 的转录、合成和释放。小胶质细胞衍生的 BDNF 可在与小胶质细胞共培养的背根神经节 (DRG) 神经元中发挥明显的生物作用，促进轴突生长和终末接触。此外，ACM 可引起培养的小胶质细胞中 p38MAPK 的显著磷酸化，这先于 BDNF 的爆发。anisomycin 通过激活 p38-MAPK 产生与 ACM 相似的有益作用，而 SB203580 特异性抑制 p38MAPK 则消除了 ACM 的所有积极作用，包括 BDNF 的促进作用和随后 DRG 神经元的轴突生长及其与小胶质细胞的终末接触。总之，我们的结果表明，小胶质细胞来源的神经保护主要是由损伤星形胶质细胞释放的微环境可溶性分子引起的，而 ACM 诱导小胶质细胞产生和释放 BDNF 可能是通过 p38-MAPK 信号通路介导的。因此，这些发现可能为进一步研究小胶质细胞在创伤性 CNS 损伤和神经退行性疾病修复中的有益激活作用奠定基础。
