Traumatic scratch injury in astrocytes triggers calcium influx to activate the JNK/c-Jun/AP-1 pathway and switch on GFAP expression

• Published in: Glia Vol. 61; no. 12; pp. 2063 - 2077
• Main Authors: Gao, Kai, Wang, Chen Ran, Jiang, Feng, Wong, Ann Yuen Kwan, Su, Na, Jiang, Jiao Hua, Chai, Rui Chao, Vatcher, Greg, Teng, Junlin, Chen, Jianguo, Jiang, Yu-Wu, Yu, Albert Cheung Hoi
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.12.2013; Wiley Subscription Services, Inc
• Subjects: Activator protein 1; Animals; Astrocytes - cytology; Astrocytes - metabolism; astrogliosis; Brain damage; Calcium; Calcium - metabolism; Calcium Signaling - genetics; calcium wave; Cells, Cultured; Cerebral Cortex - cytology; Cerebral Cortex - metabolism; Genes, jun - physiology; glial fibrillary acidic protein; Glial Fibrillary Acidic Protein - metabolism; glial scar; Gliosis - genetics; Gliosis - metabolism; JNK; MAP Kinase Signaling System - physiology; Mice; Mice, Inbred ICR; Transcription Factor AP-1 - genetics; Transcription Factor AP-1 - metabolism; Transcriptional Activation; calcium wave; astrogliosis; glial scar; glial fibrillary acidic protein; JNK
• ISSN: 0894-1491; 1098-1136; 1098-1136
• DOI: 10.1002/glia.22577

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. GLIA 2013;61:2063–2077