A translocator protein 18 kDa ligand, Ro5-4864, inhibits ATP-induced NLRP3 inflammasome activation
A translocator protein 18 kDa ligand, Ro5-4864, inhibits ATP-induced NLRP3 inflammasome activation
复制标题
DOI：
10.1016/j.bbrc.2016.04.080
复制
发表时间：
2016-06-03
影响因子：
3.1
通讯作者：
Yu, Seong-Woon
中科院分区：
文献类型：
--
作者：
Lee, Ji-Won;Kim, Leah Eunjung;Yu, Seong-Woon
Ro5-4864和PK11195是转运蛋白18kda （TSPO）的典型合成配体，在几种炎症性疾病模型中显示出抗炎作用；然而，它们的生化机制仍然知之甚少。nod样受体家族，pyrin结构域3 （NLRP3）炎性体激活作为先天免疫系统的一部分，已涉及多种炎症性疾病。在这里，我们首次证明了TSPO配体，特别是Ro5-4864，在THP-1和BMDM细胞中有效抑制atp诱导的NLRP3炎性体激活。进一步研究THP-1细胞的作用机制。Ro5-4864有效地减弱了NLRP3向线粒体的易位、炎症小体的组装/寡聚化、caspase-1的激活以及随后成熟形式的白介素-1 β和-18的分泌。在atp处理的细胞中，Ro5-4864也减少了线粒体超氧化物的产生，并保留了线粒体膜电位，这表明Ro5-4864可能作用于线粒体或NLRP3炎性小体信号传导的更多上游靶点。我们还观察到TSPO配体在THP-1单核细胞和巨噬细胞之间的不同作用，这表明NLRP3炎症小体信号的不同取决于细胞类型。总之，我们的新发现表明，Ro5-4864通过预防线粒体扰动有效抑制atp诱导的NLRP3炎性体激活。我们的研究结果表明，Ro5-4864是治疗NLRP3炎性小体相关疾病的有希望的候选者。(C) 2016 Elsevier Inc.版权所有。
Ro5-4864 and PK11195, prototypical synthetic ligands of translocator protein 18 kDa (TSPO), have shown anti-inflammatory effects in several models of inflammatory diseases; however, their biochemical mechanisms remain poorly understood. Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation as a part of the innate immune system, has been implicated in a variety of inflammatory diseases. Here, we demonstrate for the first time that TSPO ligands, especially Ro5-4864, potently suppressed ATP-induced NLRP3 inflammasome activation in THP-1 and BMDM cells. Detailed action mechanism was further investigated in THP-1 cells. Ro5-4864 efficiently attenuated NLRP3 translocation to mitochondria, inflammasome assembly/oligomerization, activation of caspase-1, and subsequent secretion of the mature forms of interleukin-1 beta and -18. Ro5-4864 also reduced the production of mitochondrial superoxide and preserved the mitochondrial membrane potential in ATP-treated cells, suggesting that Ro5-4864 may act on mitochondria or more upstream targets in NLRP3 inflammasome signaling. We also observed the distinct effects of the TSPO ligands between THP-1 monocytes and macrophages, which suggested different NLRP3 inflammasome signaling depending on cell type. Collectively, our novel findings demonstrate that Ro5-4864 effectively inhibited ATP-induced NLRP3 inflammasome activation through the prevention of mitochondrial perturbation. Our results indicate Ro5-4864 as a promising candidate for the treatment of NLRP3 inflammasome-related diseases. (C) 2016 Elsevier Inc. All rights reserved.