Traumatic Scratch Injury in Astrocytes Triggers Calcium Influx to Activate the JNK/c-Jun/AP-1 Pathway and Switch on GFAP Expression
Traumatic Scratch Injury in Astrocytes Triggers Calcium Influx to Activate the JNK/c-Jun/AP-1 Pathway and Switch on GFAP Expression
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星形胶质细胞的创伤性划伤会触发钙内流，激活 JNK/c-Jun/AP-1 通路并开启 GFAP 表达
DOI：
10.1002/glia.22577
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发表时间：
2013-12-01
期刊：
影响因子：
6.2
通讯作者：
Yu, Albert Cheung Hoi
中科院分区：
文献类型：
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作者：
Gao, Kai;Wang, Chen Ran;Yu, Albert Cheung Hoi
星形胶质细胞活化是导致神经胶质瘢痕形成（星形胶质细胞增生）的中枢神经系统损伤的标志。星形胶质细胞的活化涉及代谢和形态学变化，其机制复杂，应明确其作用机制，为星形胶质细胞增生的干预提供靶点。星形胶质细胞增生通常伴有胶质细胞酸性蛋白（GFAP）的上调。使用体外划痕损伤模型，我们抓伤大脑皮层星形胶质细胞的原代培养物，并观察到钙的流入，通过缝隙连接从伤口传播的波的形式。使用钙离子阻断剂BAPTA-AM和JNK抑制剂SP 600125，我们证明了钙波触发JNK的激活，然后磷酸化转录因子c-Jun，以促进AP-1与GFAP基因启动子的结合，从而开启GFAP上调。在体内刺伤模型中用BAPTA-AM阻断钙动员减少了GFAP表达和胶质瘢痕形成，表明钙信号以及下游信号分子的后续调节在脑损伤反应中起着重要作用。我们的研究结果表明，星形胶质细胞的创伤性划痕损伤引发了细胞外室的钙离子内流，并激活了JNK/c-Jun/AP-1途径以开启GFAP表达，从而确定了一种以前未报告的信号级联反应，该信号级联反应在星形胶质细胞增生和脑损伤后的生理反应中非常重要。
Astrocyte activation is a hallmark of central nervous system injuries resulting in glial scar formation (astrogliosis). The activation of astrocytes involves metabolic and morphological changes with complex underlying mechanisms, which should be defined to provide targets for astrogliosis intervention. Astrogliosis is usually accompanied by an upregulation of glial fibrillary acidic protein (GFAP). Using an in vitro scratch injury model, we scratched primary cultures of cerebral cortical astrocytes and observed an influx of calcium in the form of waves spreading away from the wound through gap junctions. Using the calcium blocker BAPTA-AM and the JNK inhibitor SP600125, we demonstrated that the calcium wave triggered the activation of JNK, which then phosphorylated the transcription factor c-Jun to facilitate the binding of AP-1 to the GFAP gene promoter to switch on GFAP upregulation. Blocking calcium mobilization with BAPTA-AM in an in vivo stab wound model reduced GFAP expression and glial scar formation, showing that the calcium signal, and the subsequent regulation of downstream signaling molecules, plays an essential role in brain injury response. Our findings demonstrated that traumatic scratch injury to astrocytes triggered a calcium influx from the extracellular compartment and activated the JNK/c-Jun/AP-1 pathway to switch on GFAP expression, identifying a previously unreported signaling cascade that is important in astrogliosis and the physiological response following brain injury.