STAT1 is a transcription factor implicated in the regulation of various cell processes such as immune response and apoptosis. Some authors report that hyper-activation of STAT1 signaling is involved in the development of neuroinflammation, a process closely related to oxidative stress. Although the role of oxidative-stress in neuroinflammation and in the pathogenesis of neurodegenerative disorders is clearly described, its influence in the regulation of STAT1 pathway is poorly understood. Herein, it is demonstrated that oxidative stress induces rapid activation of STAT1 signaling in murine microglia BV2 cells using H2O2 and hypoxia treatment. The molecular mechanism of its activation is related to S-glutathionylation on Cys324 and Cys492 residues of STAT1. These results reveal that STAT1 is a redox-sensitive protein and that its activation involves both tyrosine phosphorylation and S- glutathionylation under oxidative stress condition. Several studies report that microglia M1 activation is the hallmark of neuroinflammation and contributes to neurodegeneration and loss of neurological function. Here, the mechanisms that drive M1 microglia activation in BV2 cells under hypoxic stimulus have been analysed and correlate it to STAT1 activation. Silencing of STAT1 protein expression, hypoxia-induced M1 microglia phenotype is counteracted suggesting the strong link between STAT1 and microglia activation triggered by hypoxia. Moreover, the ability of hypoxia-activated microglia to induce neuronal apoptosis is shown using in vitro cross-talk model between BV2 and SH-SY5Y cell lines. Finally, it is revealed that a specific anti-STAT1 flavonoid myricetin is able to counteract microglia activation under hypoxia preventing neuronal death in the cross-talk cellular model.
|Titolo:||Redox regulation of STAT1 in microglia M1 activation|
|Data di pubblicazione:||2020|
|Appare nelle tipologie:||07.13 Doctoral Thesis|