Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, 171 76, Stockholm, Sweden.
Nature. 2011 Apr 21;472(7343):319-24. doi: 10.1038/nature09788. Epub 2011 Mar 9.
Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-δ-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson's disease (PD) and the frontal cortex of individuals with Alzheimer's disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.
小胶质细胞的激活和炎症介导的神经毒性被认为在几种神经退行性疾病的发病机制中起决定性作用。激活的小胶质细胞释放可能具有神经毒性的促炎因子。在这里，我们表明，凋亡细胞死亡的已知执行者 caspase-8 和 caspase-3/7 的有序激活通过蛋白激酶 C（PKC）-δ 依赖性途径调节小胶质细胞的激活。我们发现，用各种炎症原刺激小胶质细胞会在体外和体内激活 caspase-8 和 caspase-3/7，但不会引发细胞死亡。敲低或化学抑制这些 Caspase 中的任何一种都会阻碍小胶质细胞的激活，从而减少神经毒性。我们观察到这些 Caspase 在帕金森病（PD）患者的腹侧中脑和阿尔茨海默病（AD）患者的额皮质中的小胶质细胞中被激活。总之，我们表明 caspase-8 和 caspase-3/7 参与调节小胶质细胞的激活。我们得出结论，抑制这些 Caspase 可能通过靶向小胶质细胞而不是神经元本身来提供神经保护。
