STAT1 drives M1 microglia activation and neuroinflammation under hypoxia.

Microglia are resident immune cells that act as the first active defence in the central nervous system. These cells constantly monitor the tissue microenvironment and rapidly react in response to hypoxia, infection and injuries. Hypoxia in the brain has been detected in several neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease and Huntington's disease. Hypoxic conditions activate microglia cells towards M1 phenotype resulting in oxidative stress and the release of pro-inflammatory cytokines. Recently, we have demonstrated that oxidative stress induces S-glutathionylation of the STAT1 and hyper-activates its signaling in microglia BV2 cells pointing out the importance of this transcription factor in neuroinflammation. In this paper we analyse the cellular mechanisms that drive M1 microglia activation in BV2 cells in response to hypoxia correlating it to STAT1 activation. The analysis of the molecular mechanism of STAT1 signaling reveals that hypoxia generates oxidative stress and induces both phosphorylation and S-glutathionylation of STAT1 that are responsible of its aberrant activation. The silencing of STAT1 protein expression counteracts hypoxia-M1 microglia phenotype suggesting the strong link between hypoxia-STAT1 and STAT1-microglia activation.