Abstract
BackgroundReactive astrogliosis is a ubiquitous but poorly understood hallmark of central nervous system pathologies such as trauma and neurodegenerative diseases. In vitro and in vivo studies have identified proinflammatory cytokines and chemokines as mediators of astrogliosis during injury and disease; however, the molecular mechanism remains unclear. In this study, we identify astrocyte elevated gene-1 (AEG-1), a human immunodeficiency virus 1 or tumor necrosis factor α-inducible oncogene, as a novel modulator of reactive astrogliosis. AEG-1 has engendered tremendous interest in the field of cancer research as a therapeutic target for aggressive tumors. However, little is known of its role in astrocytes and astrocyte-mediated diseases. Based on its oncogenic role in several cancers, here we investigate the AEG-1-mediated regulation of astrocyte migration and proliferation during reactive astrogliosis.MethodsAn in vivo brain injury mouse model was utilized to show AEG-1 induction following reactive astrogliosis. In vitro wound healing and cell migration assays following AEG-1 knockdown were performed to analyze the role of AEG-1 in astrocyte migration. AEG-1-mediated regulation of astrocyte proliferation was assayed by quantifying the levels of cell proliferation markers, Ki67 and proliferation cell nuclear antigen, using immunocytochemistry. Confocal microscopy was used to evaluate nucleolar localization of AEG-1 in cultured astrocytes following injury.ResultsThe in vivo mouse model for brain injury showed reactive astrocytes with increased glial fibrillary acidic protein and AEG-1 colocalization at the wound site. AEG-1 knockdown in cultured human astrocytes significantly reduced astrocyte migration into the wound site and cell proliferation. Confocal analysis showed colocalization of AEG-1 to the nucleolus of injured cultured human astrocytes.ConclusionsThe present findings report for the first time the novel role of AEG-1 in mediating reactive astrogliosis and in regulating astrocyte responses to injury. We also report the nucleolar localization of AEG-1 in human astrocytes in response to injury. Future studies may be directed towards elucidating the molecular mechanism of AEG-1 action in astrocytes during reactive astrogliosis.
Highlights
Reactive astrogliosis is a ubiquitous but poorly understood hallmark of central nervous system pathologies such as trauma and neurodegenerative diseases
An in vivo brain injury mouse model of reactive astrogliosis was used to investigate the change in Astrocyte elevated gene-1 (AEG-1) astrocyte expression in response to injury in an intact healthy central nervous system (CNS)
While AEG-1 was first described as an human immunodeficiency virus (HIV)-1-inducible transcript in astrocytes [1], this is the first report that describes a critical role of AEG-1 in reactive astrogliosis, the first line of defense for any CNS injury [23]
Summary
Reactive astrogliosis is a ubiquitous but poorly understood hallmark of central nervous system pathologies such as trauma and neurodegenerative diseases. We identify astrocyte elevated gene-1 (AEG-1), a human immunodeficiency virus 1 or tumor necrosis factor α-inducible oncogene, as a novel modulator of reactive astrogliosis. Astrocytes, as the most abundant cell type in the brain, respond to all forms of central nervous system (CNS) pathologies, from infection, injury and ischemia to neurodegenerative diseases, by a process commonly referred to as reactive astrogliosis. During this process, astrocytes undergo spectrum of changes in their molecular expression patterns and morphology, leading to both beneficial and detrimental effects on surrounding neural and nonneural cells. We initiate studies to assess the role of AEG-1 in human astrocytes for mediating injury responses and further discuss their implications for HIV-1 CNS infection
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