Tripartite-Motif Protein 30 Negatively Regulates NLRP3 Inflammasome Activation by Modulating Reactive Oxygen Species Production
Tripartite-Motif Protein 30 Negatively Regulates NLRP3 Inflammasome Activation by Modulating Reactive Oxygen Species Production
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DOI：
10.4049/jimmunol.1001099
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发表时间：
2010-12-15
影响因子：
4.4
通讯作者：
Sun, Bing
中科院分区：
文献类型：
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作者：
Hu, Yu;Mao, Kairui;Sun, Bing
NLR家族，含pyrin结构域3（NLRP 3）炎性体对于胱天蛋白酶-1活化和pro-IL-1 β的蛋白水解加工至关重要。然而，调节NLRP 3炎性小体激活的机制仍不清楚。在本文中，我们证明了三部分基序蛋白30（TRIM 30）负调控NLRP 3炎性小体激活。在用ATP（NLRP 3炎性体的激动剂）刺激后，TRIM 30的敲低在J774细胞和骨髓源性巨噬细胞中增强了半胱天冬酶-1活化并增加了IL-1 β的产生。与ATP类似，TRIM 30的敲低增加了由其他NLRP 3炎性体激动剂（包括尼日利亚菌素、白藜芦醇和二氧化硅）触发的半胱天冬酶-1活化和IL-1 β产生。TRIM 30敲低细胞中活性氧的产生增加，并且其增加是增强NLRP 3炎性小体活化所需的，因为抗氧化剂处理阻断了过量的IL-1 β产生。相反，TRIM 30的过表达减弱了活性氧的产生和NLRP 3炎性小体的活化。最后，在晶体诱导的NLRP 3炎性小体依赖性腹膜炎模型中，TRIM 30转基因小鼠中，与非转基因同窝小鼠相比，酒石酸诱导的中性粒细胞通量和IL-1 β产生显著减少。总之，我们的研究结果表明，TRIM 30是NLRP 3炎性小体激活的负调节因子，并提供了TRIM 30在维持炎症反应中的作用的见解。免疫学杂志，2010，185：7699-7705。
The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome is critical for caspase-1 activation and the proteolytic processing of pro-IL-1 beta. However, the mechanism that regulates NLRP3 inflammasome activation remains unclear. In this paper, we demonstrate that tripartite-motif protein 30 (TRIM30) negatively regulates NLRP3 inflammasome activation. After stimulation with ATP, an agonist of the NLRP3 inflammasome, knockdown of TRIM30 enhanced caspase-1 activation and increased production of IL-1 beta in both J774 cells and bone marrow-derived macrophages. Similarly with ATP, knockdown of TRIM30 increased caspase-1 activation and IL-1 beta production triggered by other NLRP3 inflammasome agonists, including nigericin, monosodium urate, and silica. Production of reactive oxygen species was increased in TRIM30 knockdown cells, and its increase was required for enhanced NLRP3 inflammasome activation, because antioxidant treatment blocked excess IL-1 beta production. Conversely, overexpression of TRIM30 attenuated reactive oxygen species production and NLRP3 inflammasome activation. Finally, in a crystal-induced NLRP3 inflammasome-dependent peritonitis model, monosodium urate-induced neutrophil flux and IL-1 beta production was reduced significantly in TRIM30 transgenic mice as compared with that in their nontransgenic littermates. Taken together, our results indicate that TRIM30 is a negative regulator of NLRP3 inflammasome activation and provide insights into the role of TRIM30 in maintaining inflammatory responses. The Journal of Immunology, 2010, 185: 7699-7705.