FOXO3a inhibits TNF-α- and IL-1β-induced astrocyte proliferation: Implication for reactive astrogliosis

Reactive astrogliosis is one of the pathological hallmarks of neurodegenerative diseases. Inflammatory cytokines, such as TNF-α and IL-1β, have been shown to mediate the reactive astrogliosis in neurodegenerative diseases; however, the molecular mechanism remains unclear. In this study, we investigated the role of transcription factor FOXO3a on astrocyte proliferation, one primary aspect of severe reactive astrogliosis. Our results confirmed that TNF-α and IL-1β increased astrocyte proliferation, as determined by Ki67 and BrdU immunostaining. Furthermore, we found that cytokine-mediated astrocyte proliferation was accompanied by an increase of the phosphorylation and reduced nuclear expression of FOXO3a. Intracranial injection of TNF-α and IL-1β induced astrocyte proliferation and hypertrophy, which was associated with reduced nuclear expression of Foxo3a in astrocytes. To determine the function of FOXO3a in astrocyte proliferation, wild type FOXO3a was overexpressed with adenovirus, which subsequently upregulated p27Kip1 and Gadd45α, and significantly inhibited cytokine-induced astrocyte proliferation. In contrast, overexpression of dominant negative FOXO3a decreased p27Kip1, upregulated cyclin D1 and promoted astrocyte proliferation. Along the same line, astrocytes isolated from Foxo3a-null mice have higher proliferative potential. In response to intracranial injection of cytokines, Foxo3a-null mice manifested severe astrogliosis in vivo. In conclusion, FOXO3a is important in restraining astrocyte proliferation during proinflammatory cytokine stimulation and loss of function of FOXO3a may be responsible for the proliferation of astrocytes in the severe form of reactive astrogliosis. Understanding the key regulatory role of FOXO3a in reactive astrogliosis may provide a novel therapeutic target during neuroinflammation.