BRD4 suppression alleviates cerebral ischemia-induced brain injury by blocking glial activation via the inhibition of inflammatory response and pyroptosis

Abstract

Ischemic stroke is a major cause of death and disability worldwide. Hyperneuroinflammation significantly contributes to ischemic stroke. Bromodomain-containing protein 4 (BRD4) is a member of the Bromo and Extra-Terminal (BET) family, and promotes inflammatory response in various types of tissue and cells. Thereby, we examined the contribution of BRD4 after cerebral ischemic/reperfusion (I/R) injury in a mouse middle cerebral artery occlusion (MCAO) model. Here, we showed that BRD4 expression was correlated with glial activation and cerebral I/R injury after MCAO in mice. Intriguingly, we found that BRD4 inhibition using its selective inhibitor, JQ1, showed a protective role in cerebral I/R injury in mice. Suppressing BRD4 by JQ1 reduced the infarction volume, brain water contents and neurological deficit score of MCAO mice. In addition, MCAO-induced glial activation was also blunted by JQ1, as proved by the significantly reduced expression of glial fibrillary acidic protein (GFAP) and Iba-1. Consistently, JQ1 treatment decreased the expression of pro-inflammatory factors by blocking nuclear factor kappa B (NF-κB) signaling. Furthermore, inflammasome activation and pyroptosis found in MCAO mice were markedly attenuated by JQ1, which were through suppressing the expression of NLRP3 (nucleotide-binding domain, leucine-rich repeat containing protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), Caspase-1 and GSDMD (gasdermin D). The protective effects of BRD4 inhibition on cerebral ischemia-induced brain injury were verified in astrocytes and microglial cells via the inhibition of inflammation and pyroptosis. In summary, blocking BRD4 expression might serve as a potential therapeutic strategy for stroke therapy.