Histone deacetylases 3 (HDAC3) modulates the acetylation state of
histone and non-
histone proteins and could be a powerful regulator of the inflammatory process in
stroke.
Inflammasome activation is a ubiquitous but poorly understood consequence of
acute ischemic stroke. Here, we investigated the potential contributions of HDAC3 to
inflammasome activation in primary cultured microglia and experimental
stroke models. In this study, we documented that HDAC3 expression was increased in microglia of mouse experimental
stroke model.
Intraperitoneal injection of
RGFP966 (a selective inhibitor of HDAC3) decreased
infarct size and alleviated neurological deficits after the onset of
middle cerebral artery occlusion (MCAO). In vitro data indicated that LPS stimulation evoked a time-dependent increase of HDAC3 and absent in
melanoma 2 (AIM2)
inflammasome in primary cultured microglia. Interestingly, AIM2 was subjected to spatiotemporal regulation by
RGFP966. The ability of
RGFP966 to inhibit the AIM2
inflammasome was confirmed in an experimental mouse model of
stroke. As expected, AIM2 knockout mice also demonstrated significant resistance to
ischemia injury compared with their wild-type littermates.
RGFP966 failed to exhibit extra protective effects in AIM2-/-
stroke mice. Furthermore, we found that
RGFP966 enhanced STAT1 acetylation and subsequently attenuated STAT1 phosphorylation, which may at least partially contributed to the negative regulation of AIM2 by
RGFP966. Together, we initially found that
RGFP966 alleviated the inflammatory response and protected against
ischemic stroke by regulating the AIM2
inflammasome.