Irf8 exacerbates hypertensive intracerebral hemorrhage by mediating a pro-inflammatory phenotype of microglia through the Stat1/Trim5 axis

Interferon regulatory factor 8 (Irf8) is a transcription factor expressed only in the microglia in the brain and directs the expression of many genes that serve microglial functions. This report investigates the role of Irf8 in microglia during the progression of hypertensive intracerebral hemorrhage (ICH). L-NAME and angiotensin II initiated the ICH mouse model after stereotactic injection of knockdown and overexpression vectors. Inflammatory responses were induced in the mouse microglia cell line BV-2 using lipopolysaccharide (LPS), and lentiviral infection was conducted to manipulate gene expression. Irf8 was significantly overexpressed in the brain tissues of ICH mice and LPS-induced BV-2 cells. Downregulation of Irf8 hampered microglial M1 polarization and the inflammatory response and partially alleviated limb dysfunction caused by neurological impairment resulting from ICH. Irf8 interacted with the signal transducer and activator of transcription 1 (Stat1), thus mediating the transcriptional activation of Stat1 on tripartite motif-containing protein 5 (Trim5) in microglia. Overexpression of Trim5 reversed the inhibitory effect of sh-Irf8 on the inflammatory response in microglia and exacerbated cerebral hemorrhage in ICH mice. Thus, it was suggested that Irf8 overexpression activated the Stat1/Trim5 axis and mediated a microglial proinflammatory phenotype, thereby exacerbating hypertensive ICH.