title: Traumatic scratch injury in astrocytes triggers calcium influx to activate the JNK/c-Jun/AP-1 pathway and switch on GFAP expression.
abstract: 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.
authors.affiliation: Neuroscience Research Institute, Key Laboratory for Neuroscience (Ministry of Education), Key Laboratory for Neuroscience (National Health and Family Planning Commission), Department of Neurobiology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Gao
authors.forename: Chen Ran
authors.initials: CR
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Jiang
authors.forename: Ann Yuen Kwan
authors.initials: AY
authors.lastname: Wong
authors.forename: Na
authors.initials: N
authors.lastname: Su
authors.forename: Jiao Hua
authors.initials: JH
authors.lastname: Jiang
authors.forename: Rui Chao
authors.initials: RC
authors.lastname: Chai
authors.forename: Greg
authors.initials: G
authors.lastname: Vatcher
authors.forename: Junlin
authors.initials: J
authors.lastname: Teng
authors.forename: Jianguo
authors.initials: J
authors.lastname: Chen
authors.forename: Yu-Wu
authors.initials: YW
authors.lastname: Jiang
authors.forename: Albert Cheung Hoi
authors.initials: AC
authors.lastname: Yu
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D016758:Genes, jun / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism*; D005911:Gliosis / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008813:Mice, Inbred ICR; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D005904:Glial Fibrillary Acidic Protein; D018808:Transcription Factor AP-1; D002118:Calcium
keywords: JNK; astrogliosis; calcium wave; glial fibrillary acidic protein; glial scar