Biochemical and Biophysical Research Communications
BRD4 suppression alleviates cerebral ischemia-induced brain injury by blocking glial activation via the inhibition of inflammatory response and pyroptosis
Introduction
Stroke is a major cause of mortality and disability in the world, and the ischemic stroke accounts for >80% of total stroke [1]. Astrocytes and microglia, the major cellular contributors to post-injury inflammation, have the potential to function as markers of disease onset and progression and to contribute to neurological outcome of acute brain injury [2,3]. After acute brain injury, these resident cells are rapidly and significantly activated, which then undergo dramatic morphological and phenotypic alterations [4]. The inflammatory microenvironment generated by glial cells has been considered to participate in blood-brain barrier (BBB) after ischemic stroke [5]. However, the molecular mechanism of activated glia on cerebral I/R injury remains to be further explored.
Pyroptosis is reported as a pro-inflammatory form of cell death and a regulated form of necrosis, which is distinct from other forms of cell death related to inflammasome activation [6,7]. The inflammasome acts as a sensor to detect cellular damage danger signals, and results in the excessive release of potent pro-inflammatory cytokines, contributing to inflammation-regulated organ injury [6,8]. Accumulating studies have indicated that this novel type of cell death plays a pivotal role in the pathogenesis of central nervous system diseases, including cerebral I/R injury, which is characterized by neuroinflammation [9,10]. Moreover, a range of cell types in central nervous system might undergo inflammasome-triggered pyroptosis, including astrocytes and microglia [11,12]. Bromodomain-containing protein 4 (BRD4), as a member of the Bromo and Extra-Terminal (BET) family, may bind to acetylated histones and transcription factors through bromodomains and modulate various pathophysiological activities such as inflammation [13]. Suppressing BRD4 by its selective inhibitor of JQ1 was suggested to alleviate lipopolysaccharides-triggered expression of pro-inflammatory cytokines [14]. Recently, growing evidence suggest that JQ1 treatment blunt osteoarthritis and rheumatoid arthritis progression partly through inflammation inhibition [15,16]. Also, spinal cord injury was also found to be repressed by JQ1 mainly via blocking microglial inflammatory response [17]. Herein, we hypothesized that BRD4 suppression might be a promising therapeutic target against ischemic stroke.
In this study, we found that BRD4 expression was associated with cerebral I/R injury in MCAO mice. Blunting BRD4 by JQ1 alleviated ischemic stroke in mice following MCAO by reducing glial activation, inflammation and pyroptosis, which indicated that BRD4 might serve as a promising therapeutic target for stroke treatment.
Section snippets
Animals and MCAO model
Male C57BL/6 mice (6–8 weeks old) were purchased from the Academy of Military Medical Science (Beijing, China). These mice were maintained in a specific pathogen-free (SPF) animal facility. The animal experiments were approved by the Animal Ethics Committee of Changhai Hospital, Naval Medical University (Shanghai, China) and were performed in accordance with animal care guidelines. Mice were randomly divided into 4 groups: 1) Sham without JQ1 treatment; 2) Sham with JQ1 treatment; 3) MCAO
BRD4 expression is induced following reperfusion in a mouse MCAO model
In ischemic cortex at 6 h, 12 h, 24 h, 72 h and 7 d after MCAO, the number of PI-positive cells was gradually increased, and peaked at 72 h (3 d) in the peri-infarct area after MCAO, indicating the cell death and brain injury triggered by MCAO (Fig. 1A and B). Then, BRD4 expression from mRNA and protein levels in the lateral cortex tissues of peri-infarct area were progressively up-regulated and reached to the highest levels at 3 d following MCAO (Fig. 1C and D). Immunofluorescent results
Discussion
Deleterious glia activation is crucially involved in the pathophysiology of cerebral ischemia. Activated glial cells have been reported in peri-infarct areas in clinical stroke and are considered to orchestrate neuronal damage in the penumbra [4,26]. Inflammation is a critical contributor to the pathogenesis of ischemic stroke. The deleterious effects of the inflammatory response following cerebral ischemia are significantly regulated by glial cells in brain, which release cytokines or
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Yi Zhou and Yang Gu are co-first authors.