The HDAC3 inhibitor RGFP966 ameliorated ischemic brain damage by downregulating the AIM2 inflammasome.
The HDAC3 inhibitor RGFP966 ameliorated ischemic brain damage by downregulating the AIM2 inflammasome.
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HDAC3 抑制剂 RGFP966 通过下调 AIM2 炎症小体来改善缺血性脑损伤。
DOI：
10.1096/fj.201900394rrr
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Xu Yun
中科院分区：
文献类型：
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作者：
Zhang Mei-Juan;Zhao Qiu-Chen;Xia Ming-Xu;Chen Jian;Chen Yan-Ting;Cao Xiang;Liu Yi;Yuan Zeng-Qiang;Wang Xiao-Ying;Xu Yun
组蛋白去乙酰化酶3（HDAC 3）调节组蛋白和非组蛋白蛋白的乙酰化状态，可能是卒中炎症过程的有力调节剂。炎性小体激活是急性缺血性卒中的普遍存在但知之甚少的后果。在这里，我们研究了HDAC 3在原代培养的小胶质细胞和实验性中风模型中对炎性小体激活的潜在贡献。在这项研究中，我们记录了HDAC 3在小鼠实验性中风模型的小胶质细胞中的表达增加。腹膜内注射RGFP 966（HDAC 3的选择性抑制剂）可减少脑梗死面积，减轻大脑中动脉闭塞（MCAO）后的神经功能缺损。体外数据表明，LPS刺激引起原代培养的小胶质细胞中HDAC 3的时间依赖性增加，并且在黑素瘤2（AIM 2）炎性小体中不存在。有趣的是，AIM 2受到RGFP 966的时空调控。RGFP 966抑制AIM 2炎性小体的能力在实验性中风小鼠模型中得到证实。正如预期的那样，AIM 2基因敲除小鼠与其野生型同窝小鼠相比，也表现出对缺血损伤的显著抗性。RGFP 966在AIM 2 −/−中风小鼠中未能表现出额外的保护作用。此外，我们发现RGFP 966增强了STAT 1的乙酰化，随后减弱了STAT 1的磷酸化，这可能至少部分导致了RGFP 966对AIM 2的负调控。总之，我们最初发现RGFP 966通过调节AIM 2炎性体减轻炎症反应并保护缺血性卒中。
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.