CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilhã, Portugal.
Faculty of Health Sciences, University of Beira Interior, 6201-506 Covilhã, Portugal.
Cells. 2023 Dec 29;13(1):74. doi: 10.3390/cells13010074.
Overactivation of microglial cells seems to play a crucial role in the degeneration of dopaminergic neurons occurring in Parkinson's disease. We have previously demonstrated that glial cell line-derived neurotrophic factor (GDNF) present in astrocytes secretome modulates microglial responses induced by an inflammatory insult. Therefore, astrocyte-derived soluble factors may include relevant molecular players of therapeutic interest in the control of excessive neuroinflammatory responses. However, in vivo, the control of neuroinflammation is more complex as it depends on the interaction between different types of cells other than microglia and astrocytes. Whether neurons may interfere in the astrocyte-microglia crosstalk, affecting the control of microglial reactivity exerted by astrocytes, is unclear. Therefore, the present work aimed to disclose if the control of microglial responses mediated by astrocyte-derived factors, including GDNF, could be affected by the crosstalk with neurons, impacting GDNF's ability to protect dopaminergic neurons exposed to a pro-inflammatory environment. Also, we aimed to disclose if the protection of dopaminergic neurons by GDNF involves the modulation of microglial cells. Our results show that the neuroprotective effect of GDNF was mediated, at least in part, by a direct action on microglial cells through the GDNF family receptor α-1. However, this protective effect seems to be impaired by other mediators released in response to the neuron-astrocyte crosstalk since neuron-astrocyte secretome, in contrast to astrocytes secretome, was unable to protect dopaminergic neurons from the injury triggered by lipopolysaccharide-activated microglia. Supplementation with exogenous GDNF was needed to afford protection of dopaminergic neurons exposed to the inflammatory environment. In conclusion, our results revealed that dopaminergic protective effects promoted by GDNF involve the control of microglial reactivity. However, endogenous GDNF is insufficient to confer dopaminergic neuron protection against an inflammatory insult. This reinforces the importance of further developing new therapeutic strategies aiming at providing GDNF or enhancing its expression in the brain regions affected by Parkinson's disease.
小胶质细胞的过度激活似乎在帕金森病中多巴胺能神经元的退化中起着关键作用。我们之前已经证明，星形胶质细胞分泌组中的胶质细胞系源性神经营养因子 (GDNF) 调节由炎症损伤诱导的小胶质细胞反应。因此，星形胶质细胞衍生的可溶性因子可能包括控制过度神经炎症反应的治疗相关分子。然而，在体内，神经炎症的控制更为复杂，因为它取决于除小胶质细胞和星形胶质细胞以外的不同类型细胞之间的相互作用。神经元是否可以干扰星形胶质细胞-小胶质细胞的串扰，从而影响星形胶质细胞对小胶质细胞反应的控制，目前尚不清楚。因此，本研究旨在揭示星形胶质细胞衍生因子（包括 GDNF）介导的小胶质细胞反应的控制是否可以受到神经元-星形胶质细胞串扰的影响，从而影响 GDNF 保护暴露于促炎环境中的多巴胺能神经元的能力。此外，我们旨在揭示 GDNF 对多巴胺能神经元的保护是否涉及小胶质细胞的调节。我们的研究结果表明，GDNF 的神经保护作用至少部分是通过 GDNF 家族受体 α-1 对小胶质细胞的直接作用介导的。然而，这种保护作用似乎受到神经元-星形胶质细胞串扰中释放的其他介质的损害，因为与星形胶质细胞分泌组相比，神经元-星形胶质细胞分泌组无法保护多巴胺能神经元免受脂多糖激活的小胶质细胞引发的损伤。需要补充外源性 GDNF 才能为暴露于炎症环境中的多巴胺能神经元提供保护。总之，我们的研究结果表明，GDNF 促进的多巴胺能保护作用涉及对小胶质细胞反应的控制。然而，内源性 GDNF 不足以赋予多巴胺能神经元对抗炎症损伤的保护作用。这进一步强调了开发旨在提供 GDNF 或增强其在帕金森病受影响脑区表达的新治疗策略的重要性。
