All-Trans Retinoic Acid Enhances both the Signaling for Priming and the Glycolysis for Activation of NLRP3 Inflammasome in Human Macrophage
All-Trans Retinoic Acid Enhances both the Signaling for Priming and the Glycolysis for Activation of NLRP3 Inflammasome in Human Macrophage
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DOI：
10.3390/cells9071591
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发表时间：
2020-07-01
期刊：
影响因子：
6
通讯作者：
Benko, Szilvia
中科院分区：
文献类型：
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作者：
Alatshan, Ahmad;Kovacs, Gergo E.;Benko, Szilvia
全反式视黄酸 (ATRA) 是维生素 A 的衍生物，具有许多重要的生物学功能，包括调节免疫反应。 ATRA 作用通过视黄酸受体介导，视黄酸受体充当核受体，调节细胞核中的基因转录或调节细胞质中的信号转导。 NLRP3 炎症小体是一种多蛋白复合物，可被多种刺激激活，包括病原体或危险相关分子。 IL-1β 的产生需要炎症小体的激活，IL-1β 可驱动感染性或非感染性无菌炎症的炎症反应。在这里，我们发现，在人单核细胞来源的巨噬细胞中，LPS (100ng/mL) 激活 2、6、12 和 24 小时后，ATRA 可延长 IL-6 和 IL-1 beta 的表达。我们首次描述了 ATRA 调节 NLRP3 炎症小体功能所需的启动和激活信号。 ATRA 单独诱导 NLRP3 表达，并通过调节 NF-κ B、p38 和 ERK 等信号转导途径增强 LPS 诱导的 NLRP3 和 pro-IL-1 beta 表达。我们发现 ATRA 通过抑制 Akt-mTOR-STAT3 信号轴来减轻 IL-10 抗炎细胞因子对 NLRP3 炎症小体功能的负反馈环路效应。我们还提供证据表明 ATRA 增强己糖激酶 2 的表达，并将 LPS 激活的巨噬细胞的代谢转向糖酵解，从而导致 NLRP3 炎症小体的激活。
All-trans retinoic acid (ATRA) is a derivative of vitamin A that has many important biological functions, including the modulation of immune responses. ATRA actions are mediated through the retinoic acid receptor that functions as a nuclear receptor, either regulating gene transcription in the nucleus or modulating signal transduction in the cytoplasm. NLRP3 inflammasome is a multiprotein complex that is activated by a huge variety of stimuli, including pathogen- or danger-related molecules. Activation of the inflammasome is required for the production of IL-1 beta, which drives the inflammatory responses of infectious or non-infectious sterile inflammation. Here, we showed that ATRA prolongs the expression of IL-6 and IL-1 beta following a 2-, 6-, 12-, and 24-h LPS (100ng/mL) activation in human monocyte-derived macrophages. We describe for the first time that ATRA modulates both priming and activation signals required for NLRP3 inflammasome function. ATRA alone induces NLRP3 expression, and enhances LPS-induced expression of NLRP3 and pro-IL-1 beta via the regulation of signal transduction pathways, like NF-kappa B, p38, and ERK. We show that ATRA alleviates the negative feedback loop effect of IL-10 anti-inflammatory cytokine on NLRP3 inflammasome function by inhibiting the Akt-mTOR-STAT3 signaling axis. We also provide evidence that ATRA enhances hexokinase 2 expression, and shifts the metabolism of LPS-activated macrophages toward glycolysis, leading to the activation of NLRP3 inflammasome.