The neuroprotection of progesterone against Aβ-induced NLRP3-Caspase-1 inflammasome activation via enhancing autophagy in astrocytes
The neuroprotection of progesterone against Aβ-induced NLRP3-Caspase-1 inflammasome activation via enhancing autophagy in astrocytes
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DOI：
10.1016/j.intimp.2019.05.054
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发表时间：
2019-09-01
影响因子：
5.6
通讯作者：
Hou, Yanning
中科院分区：
文献类型：
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作者：
Hong, Yang;Liu, Yunjiang;Hou, Yanning
神经炎症和自噬功能障碍参与了阿尔茨海默病（AD）的病理过程。黄体酮（PG）是一种神经活性类固醇，在改善阿尔茨海默病中发挥着独特的神经保护作用。nod样受体pyrin 3 (NLRP3)-Caspase-1炎性体与AD的病理过程有特殊的相关性。然而，PG在调节NLRP3-Caspase-1炎性体中的确切作用仍有待阐明。我们通过激活NLRP3-Caspase-1炎性体，证实了β上调星形胶质细胞中IL-1 β的表达。然而，雷帕霉素（Rapamycin， RAPA）通过调节NLRP3-Caspase-1炎性体，有效地抑制了A β -、脂多糖（LPS）诱导的IL-1 β表达。值得注意的是，PG显著抑制A β诱导的NLRP3-Caspase-1炎性体激活。自噬抑制剂3-MA阻断PG介导NLRP3炎性体和IL-1 β加工的保护作用。综上所述，我们的观察结果表明，自噬-溶酶体途径是调节A β诱导的星形胶质细胞NLRP3-Caspase-1炎性体激活的一种特定分子机制，特别是揭示了PG在调节导致神经炎症序列事件的上游信号传导中的潜在神经保护作用。PG调节NLRP3-Caspase-1炎性体的神经保护机制可能是改善AD病理过程的潜在治疗靶点。
Neuroinflammation and autophagy dysfunction are known to be involved in the pathological procession of Alzheimer's disease (AD). Progesterone (PG), neuroactive steroids, exerts a characteristic neuroprotective function in improving AD syndrome. The NOD-like receptor pyrin 3 (NLRP3)-Caspase-1 inflammasome has specific relevance to AD pathological procession. However, the exact role of PG in regulating NLRP3-Caspase-1 inflammasome remains to be elucidated. We demonstrated A beta up-regulated IL-1 beta expression in astrocytes by activating NLRP3-Caspase-1 inflammasome. However, pharmacological activation of autophagy by Rapamycin (RAPA) efficiently suppressed A beta-, lipopolysaccharides (LPS)-induced IL-1 beta expression via regulating NLRP3-Caspase-1 inflammasome in astrocytes. Remarkably, PG significantly inhibited A beta-induced NLRP3-Caspase-1 inflammasome activation. Autophagy inhibitor 3-MA blocked the protective effects of PG in mediating NLRP3 inflammasome and IL-1 beta processing. Taken together, our observations suggest that autophagy-lysosome pathway is one specific molecular mechanism in regulating A beta-induced NLRP3-Caspase-1 inflammasome activation in astrocytes, particularly uncover the potential neuroprotection of PG in regulating upstream signaling leading to the sequence events of neuroinflammation. That neuroprotective mechanism of PG in regulating NLRP3-Caspase-1 inflammasome can be a potential therapeutic target for ameliorating the pathological procession of AD.