YAP Is a Critical Inducer of SOCS3, Preventing Reactive Astrogliosis.
YAP Is a Critical Inducer of SOCS3, Preventing Reactive Astrogliosis.
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YAP 是 SOCS3 的关键诱导剂，可预防反应性星形胶质细胞增生。
DOI：
10.1093/cercor/bhv292
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发表时间：
2016-05
期刊：
影响因子：
--
通讯作者：
Xiong WC
中科院分区：
文献类型：
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作者：
Huang Z;Wang Y;Hu G;Zhou J;Mei L;Xiong WC
YAP是河马途径的关键转录辅因子，对多个器官的发育至关重要。然而，它在发育中的大脑中的作用仍然知之甚少。在此，我们发现YAP在星形胶质细胞中高表达，YAP缺失在培养和体内均可促进星形胶质细胞的激活，这与小胶质细胞的激活有关。在分子水平上，干扰素β或睫状神经营养因子激活星形胶质细胞中的YAP，这是干扰素β或睫状神经营养因子诱导细胞因子信号转导抑制因子3(JAK-STAT)炎症通路负调节因子所必需的。因此，YAP−/−星形胶质细胞表现出JAK-STAT炎症通路的过度激活和反应性星形胶质细胞增生。SOCS3在YAP−/−星形胶质细胞中的表达阻止了STAT3的过度激活，并部分恢复了星形胶质细胞的激活。最后，在YAP脑选择性基因敲除小鼠中，反应性星形胶质细胞增多症与血脑屏障功能障碍有关。综上所述，这些结果确认了YAP在预防反应性星形胶质细胞增生中未知的功能，并揭示了YAP-SOCs负性控制神经炎症的途径。
Yes-associated protein (YAP) is a key transcriptional cofactor of the Hippo pathway, critical for the development of multiple organs. However, its role in the developing brain remains poorly understood. Here, we found that YAP was highly expressed in astrocytes and YAP deletion elevated the astrocytic activation in culture and in vivo, which was associated with microglial activation. At the molecular level, YAP in astrocytes was activated by IFNβ or ciliary neurotrophic factor (CNTF), which was necessary for IFNβ or CNTF induction of the suppressor of cytokine signaling 3 (SOCS3), a negative regulator of the Janus kinase–signal transducer and activator of transcription (JAK–STAT) inflammatory pathway. YAP−/− astrocytes thus showed hyperactivation of the JAK–STAT inflammatory pathway and reactive astrogliosis. Expression of SOCS3 in YAP−/− astrocytes prevented the hyperactivation of STAT3 and partially restored the astrocytic activation. Finally, reactive astrogliosis was associated with blood–brain barrier dysfunction in YAP brain-selective knockout mice. Taken together, these results identify unrecognized functions of YAP in preventing reactive astrogliosis and reveal a pathway of YAP-SOCS for the negatively control of neuroinflammation.