CICS-UBI — Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.
Neurobiol Dis. 2012 Sep;47(3):407-15. doi: 10.1016/j.nbd.2012.04.014. Epub 2012 May 3.
Neuroinflammation is recognized as a major factor in Parkinson's disease (PD) pathogenesis and increasing evidence propose that microglia is the main source of inflammation contributing to the dopaminergic degeneration observed in PD. Several studies suggest that astrocytes could act as physiological regulators preventing excessive microglia responses. However, little is known regarding how astrocytes modulate microglial activation. In the present study, using Zymosan A-stimulated midbrain microglia cultures, we showed that astrocytes secrete factors capable of modulating microglial activation, namely its phagocytic activity and the production of reactive oxygen species since both parameters were highly diminished in cells incubated with astrocytes conditioned media (ACM). Glial cell line-derived neurotrophic factor (GDNF), cerebral dopamine neurotrophic factor (CDNF) and brain-derived neurotrophic factor (BDNF), known to have a neuroprotective role in the nigrostriatal system, are among the candidates to be astrocyte-secreted molecules involved in the modulation of microglial activation. The effect of ACM on Zymosan A-induced microglial activation was abolished when the GDNF present in the ACM was abrogated using a specific antibody, but not when ACM was neutralized with anti-CDNF, anti-BDNF or with a heat-inactivated GDNF antibody. In addition, media conditioned by astrocytes silenced for GDNF were not able to prevent microglial activation, whereas supplementation of non-conditioned media with GDNF prevented the activation of microglia evoked by Zymosan A. Taken together, these results indicate that astrocyte-derived GDNF plays a major contribution to the control of midbrain microglial activation, suggesting that GDNF can protect from neurodegeneration through the inhibition of neuroinflammation.
神经炎症被认为是帕金森病 (PD) 发病机制的一个主要因素，越来越多的证据表明，小胶质细胞是导致 PD 中观察到的多巴胺能变性的主要炎症来源。一些研究表明，星形胶质细胞可以作为生理调节剂，防止小胶质细胞过度反应。然而，关于星形胶质细胞如何调节小胶质细胞激活知之甚少。在本研究中，我们使用酵母聚糖 A 刺激的中脑小胶质细胞培养物表明，星形胶质细胞分泌能够调节小胶质细胞激活的因子，即其吞噬活性和活性氧的产生，因为与用星形胶质细胞条件培养基 (ACM) 孵育的细胞相比，这两个参数都显著降低。胶质细胞系衍生的神经营养因子 (GDNF)、脑源性多巴胺神经营养因子 (CDNF) 和脑源性神经营养因子 (BDNF)，已知在黑质纹状体系统中具有神经保护作用，是星形胶质细胞分泌的参与调节小胶质细胞激活的分子之一。当使用特异性抗体阻断 ACM 中的 GDNF 时，ACM 对酵母聚糖 A 诱导的小胶质细胞激活的作用被消除，但当 ACM 被抗 CDNF、抗 BDNF 或热失活的 GDNF 抗体中和时，这种作用不会被消除。此外，沉默 GDNF 的星形胶质细胞条件培养基不能防止小胶质细胞激活，而用 GDNF 补充非条件培养基可防止酵母聚糖 A 诱导的小胶质细胞激活。综上所述，这些结果表明，星形胶质细胞衍生的 GDNF 对控制中脑小胶质细胞激活有重要贡献，表明 GDNF 可以通过抑制神经炎症来保护神经退行性变。
