REV-ERBα agonist SR9009 suppresses IL-1β production in macrophages through BMAL1-dependent inhibition of inflammasome
REV-ERBα agonist SR9009 suppresses IL-1β production in macrophages through BMAL1-dependent inhibition of inflammasome
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DOI：
10.1016/j.bcp.2021.114701
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发表时间：
2021-07-30
影响因子：
5.8
通讯作者：
Tian, Xiao Yu
中科院分区：
文献类型：
--
作者：
Hong, Huiling;Cheung, Yiu Ming;Tian, Xiao Yu
生物钟在使生物体适应日常光/暗循环环境方面发挥着重要作用。最近的研究结果表明，生物钟不仅参与生理功能，而且还参与调节病理情况下的炎症反应。先前的研究表明，白细胞循环和促炎细胞因子分泌的时间变化可以直接受到时钟相关蛋白的调节，包括 BMAL1 和 REV-ERB α 以 24 小时振荡模式。为了研究核心时钟成分调节炎症背后的分子机制，我们重点关注巨噬细胞的炎症反应。使用野生型和骨髓选择性 BMAL1 敲除小鼠的骨髓源性巨噬细胞，我们发现炎症细胞因子（特别是 IL-1 β）的产生取决于巨噬细胞中脂多糖 (LPS) 刺激的时间。用 SR9009 药理激活 REV-ERB α 可显着抑制体外和体内 LPS 诱导的炎症。特别是，SR9009 抑制巨噬细胞中 NLRP3 介导的 IL-1β 和 IL-18 产生的作用取决于 BMAL1 表达。对 LPS 处理小鼠代谢活性的进一步分析表明，即使在 SR9009 存在的情况下，巨噬细胞中 BMAL1 的敲除也会加剧代谢低下状态，并延迟 LPS 诱导的内毒素血症的恢复。这些结果表明，REV-ERB α在内毒素诱导的炎症中具有抗炎作用，在此过程中，BMAL1通过SR9009抑制的NLRP3炎症小体途径分泌IL-1 β。
The circadian clock plays an important role in adapting organisms to the daily light/dark cycling environment. Recent research findings reveal the involvement of the circadian clock not only in physiological functions but also in regulating inflammatory responses under pathological situations. Previous studies showed that the time-of-day variance of leucocyte circulation and pro-inflammatory cytokines secretion could be directly regulated by the clock-related proteins, including BMAL1 and REV-ERB alpha in a 24-hour oscillation pattern. To investigate the molecular mechanism behind the regulation of inflammation by the core clock components, we focus on the inflammatory responses in macrophages. Using bone marrow-derived macrophages from wild type and myeloid selective BMAL1-knockout mice, we found that the production of inflammatory cytokines, particularly IL-1 beta, was dependent on the timing of the lipopolysaccharide (LPS) stimulation in macrophages. Pharmacological activation of REV-ERB alpha with SR9009 significantly suppressed the LPS-induced inflammation in vitro and in vivo. Particularly, the effect of SR9009 on inhibiting NLRP3-mediated IL-1 beta and IL-18 production in macrophages was dependent on BMAL1 expression. Further analysis of the metabolic activity in LPS-treated mice showed that knockout of BMAL1 in macrophages exacerbated the hypometabolic state and delayed the recovery from LPS-induced endotoxemia even in the presence of SR9009. These results demonstrated an anti-inflammatory role of REV-ERB alpha in endotoxin-induced inflammation, during which the secretion of IL-1 beta through the NLRP3 inflammasome pathway inhibited by SR9009 was regulated by BMAL1.