Targeting Peroxiredoxin 1 by a Curcumin Analogue, AI-44, Inhibits NLRP3 Inflammasome Activation and Attenuates Lipopolysaccharide-Induced Sepsis in Mice
Targeting Peroxiredoxin 1 by a Curcumin Analogue, AI-44, Inhibits NLRP3 Inflammasome Activation and Attenuates Lipopolysaccharide-Induced Sepsis in Mice
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姜黄素类似物 AI-44 靶向过氧化还原蛋白 1，抑制 NLRP3 炎性体激活并减轻脂多糖诱导的小鼠败血症
DOI：
10.4049/jimmunol.1700796
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发表时间：
2018-10-15
影响因子：
4.4
通讯作者：
Sun, Yang
中科院分区：
文献类型：
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作者：
Liu, Wen;Guo, Wenjie;Sun, Yang
NLRP3炎性小体的异常激活有助于各种炎症性疾病的发生和进展，使其成为非常理想的药物靶点。在这项研究中，我们筛选了一系列具有抗炎活性的小化合物，并鉴定出一种新的NLRP3炎症小体抑制剂AI-44，一种姜黄素类似物，可以选择性地抑制NLRP3炎症小体激活的信号2而不是信号1。我们发现AI-44与过氧化物还蛋白1 （PRDX1）结合，并促进PRDX1与caspase -1 （CASP1）的相互作用，从而抑制了pro-CASP1与ASC的关联。因此，NLRP3炎症小体的组装被中断，CASP1的激活被抑制。PRDX1基因敲低可明显减弱AI-44对NLRP3炎性体的抑制作用。重要的是，AI-44通过抑制NLRP3炎性体的激活，减轻了lps诱导的小鼠内毒素血症。综上所述，我们的研究突出了PRDX1作为NLRP3炎症小体激活的负调节因子，并建议AI-44作为治疗脓毒症或其他NLRP3炎症小体驱动疾病的有希望的候选化合物。
Aberrant activation of the NLRP3 inflammasome contributes to the onset and progression of various inflammatory diseases, making it a highly desirable drug target. In this study, we screened a series of small compounds with anti-inflammatory activities and identified a novel NLRP3 inflammasome inhibitor, AI-44, a curcumin analogue that selectively inhibited signal 2 but not signal 1 of NLRP3 inflammasome activation. We demonstrated that AI-44 bound to peroxiredoxin 1 (PRDX1) and promoted the interaction of PRDX1 with pro–Caspase-1 (CASP1), which led to the suppression of association of pro-CASP1 and ASC. Consequently, the assembly of the NLRP3 inflammasome was interrupted, and the activation of CASP1 was inhibited. Knockdown of PRDX1 significantly abrogated the inhibitory effect of AI-44 on the NLRP3 inflammasome. Importantly, AI-44 alleviated LPS-induced endotoxemia in mice via suppressing NLRP3 inflammasome activation. Taken together, our work highlighted PRDX1 as a negative regulator of NLRP3 inflammasome activation and suggested AI-44 as a promising candidate compound for the treatment of sepsis or other NLRP3 inflammasome-driven diseases.