Attenuation of cerebral ischemic injury in interferon regulatory factor 3-deficient rat

Abstract

Interferon regulatory factor 3 (IRF3) is a transcription factor that plays a central role in the innate immune response, apoptosis, and oncogenesis. Previous studies have shown that endogenous IRF3 does not affect stroke in mice; however, paradoxically, elevated IRF3 expression was observed in the rat brains following cerebral ischemia/reperfusion (I/R) injury, indicating that IRF3 may have different functions during stroke in rats than in mice. A clear and comprehensive study of the effect of IRF3 on stroke in rats has been hampered by the lack of an IRF3-knockout rat strain. In this study, a novel IRF3 knockout rat strain and a transgenic rat strain with neuronal-specific IRF3 over-expression (IRF3-TG) were created. Subsequently, the generated IRF3-knockout rats, the neuronal-specific IRF3 over-expressing rats and their corresponding controls were subjected to transient middle cerebral artery occlusion and followed by reperfusion, to investigate the exact role of IRF3 in cerebral I/R in rats. In contrast to the results in mice, IRF3 deficiency in rats provided significant protection against cerebral I/R injury and inhibited neuronal apoptosis, inflammation, and oxidative stress after cerebral I/R injury; the opposite patterns were observed in neuronal-specific IRF3 over-expressing rats. Taken together, these data demonstrate that IRF3 plays a negative regulatory role in cerebral I/R in rats, and IRF3 may be an attractive therapeutic target for preventing stroke. In the present study, we discovered that the transcription factor IRF3, which plays a central role in the innate immune response, apoptosis, and oncogenesis, could exacerbate cerebral ischemia/reperfusion (I/R) injury via activating caspase-dependent neuronal apoptosis, inducing inflammation and oxidative stress. These findings suggest that IRF3 may be an attractive therapeutic target for the prevention of stroke. In the present study, we discovered that the transcription factor IRF3, which plays a central role in the innate immune response, apoptosis, and oncogenesis, could exacerbate cerebral ischemia/reperfusion (I/R) injury via activating caspase-dependent neuronal apoptosis, inducing inflammation and oxidative stress. These findings suggest that IRF3 may be an attractive therapeutic target for the prevention of stroke.