3,4-亚甲二氧基-β-硝基苯乙烯通过阻断炎性体的组装来抑制 NLRP3 炎性体的激活。,Journal of Biological Chemistry

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3,4-亚甲二氧基-β-硝基苯乙烯通过阻断炎性体的组装来抑制 NLRP3 炎性体的激活。
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2014 Jan 10 , DOI: 10.1074/jbc.m113.515080
Yuan He ₁ , Saranyaraajan Varadarajan , Raúl Muñoz-Planillo , Aaron Burberry , Yuumi Nakamura , Gabriel Núñez

Affiliation

NLRP3 炎症小体是先天免疫系统的重要组成部分。NLRP3 激活是由与细菌感染或组织损伤相关的各种刺激诱导的，但其不适当的激活参与了遗传性和获得性炎症性疾病的发病机制。然而，NLRP3 被激活的机制仍然知之甚少。在这项研究中，我们通过筛选激酶抑制剂库探索了激酶在 NLRP3 炎症小体激活中的作用，并确定了 3,4-亚甲二氧基-β-硝基苯乙烯 (MNS) 作为 NLRP3 炎症小体激活的抑制剂。值得注意的是，MNS 不影响 NLRC4 或 AIM2（黑色素瘤 2 中不存在）炎症小体的激活。从机制上讲，MNS 特异性地阻止了 NLRP3 介导的 ASC 斑点形成和寡聚化，而不会阻止 NLRP3 激动剂诱导的钾外流。令人惊讶的是，报道的 MNS 靶点 Syk 激酶并没有介导 MNS 对 NLRP3 炎症小体激活的抑制活性。我们还发现 MNS 的硝基乙烯基对 MNS 的抑制活性是必不可少的。免疫沉淀、质谱和突变研究表明 NLRP3 的核苷酸结合寡聚化结构域和富含亮氨酸的重复结构域都是 MNS 的细胞内靶标。MNS 的给药也在体外抑制 NLRP3 ATPase 活性，表明 MNS 通过直接靶向 NLRP3 或 NLRP3 相关复合物来阻断 NLRP3 炎性体。

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3,4-methylenedioxy-beta-nitrostyrene inhibits NLRP3 inflammasome activation by blocking assembly of the inflammasome.

The NLRP3 inflammasome is a critical component of the innate immune system. NLRP3 activation is induced by diverse stimuli associated with bacterial infection or tissue damage, but its inappropriate activation is involved in the pathogenesis of inherited and acquired inflammatory diseases. However, the mechanism by which NLRP3 is activated remains poorly understood. In this study, we explored the role of kinases in NLRP3 inflammasome activation by screening a kinase inhibitor library and identified 3,4-methylenedioxy-beta-nitrostyrene (MNS) as an inhibitor for NLRP3 inflammasome activation. Notably, MNS did not affect the activation of the NLRC4 or AIM2 (absent in melanoma 2) inflammasome. Mechanistically, MNS specifically prevented NLRP3-mediated ASC speck formation and oligomerization without blocking potassium efflux induced by NLRP3 agonists. Surprisingly, Syk kinase, the reported target of MNS, did not mediate the inhibitory activity of MNS on NLRP3 inflammasome activation. We also found that the nitrovinyl group of MNS is essential for the inhibitory activity of MNS. Immunoprecipitation, mass spectrometry, and mutation studies suggest that both the nucleotide binding oligomerization domain and the leucine-rich repeat domain of NLRP3 were the intracellular targets of MNS. Administration of MNS also inhibited NLRP3 ATPase activity in vitro, suggesting that MNS blocks the NLRP3 inflammasome by directly targeting NLRP3 or NLRP3-associated complexes. These studies identified a novel chemical probe for studying the molecular mechanism of NLRP3 inflammasome activation which may advance the development of novel strategies to treat diseases associated with abnormal activation of NLRP3 inflammasome.

更新日期：2017-01-31

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