Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai, China.
J Immunol. 2010 Dec 15;185(12):7699-705. doi: 10.4049/jimmunol.1001099. Epub 2010 Nov 3.
The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome is critical for caspase-1 activation and the proteolytic processing of pro-IL-1β. 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-1β in both J774 cells and bone marrow-derived macrophages. Similarly with ATP, knockdown of TRIM30 increased caspase-1 activation and IL-1β 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-1β 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-1β 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.
NLR 家族，包含pyrin 结构域的 3（NLRP3）炎症小体对于半胱天冬酶-1 的激活和 pro-IL-1β 的蛋白水解加工至关重要。然而，调节 NLRP3 炎症小体激活的机制尚不清楚。在本文中，我们证明了三结构域蛋白 30（TRIM30）负调节 NLRP3 炎症小体的激活。在用 ATP 刺激后，NLRP3 炎症小体的激动剂，TRIM30 的敲低增强了半胱天冬酶-1 的激活，并增加了 J774 细胞和骨髓来源的巨噬细胞中 IL-1β 的产生。与 ATP 类似，TRIM30 的敲低增加了其他 NLRP3 炎症小体激动剂（包括 Nigericin、单钠尿酸盐和二氧化硅）引发的半胱天冬酶-1 的激活和 IL-1β 的产生。TRIM30 敲低细胞中的活性氧产生增加，并且其增加对于增强的 NLRP3 炎症小体激活是必需的，因为抗氧化剂处理阻止了过量的 IL-1β 产生。相反，TRIM30 的过表达减弱了活性氧的产生和 NLRP3 炎症小体的激活。最后，在晶体诱导的 NLRP3 炎症小体依赖性腹膜炎模型中，与非转基因同窝仔相比，单钠尿酸盐诱导的中性粒细胞流和 IL-1β 的产生在 TRIM30 转基因小鼠中显著减少。总之，我们的结果表明 TRIM30 是 NLRP3 炎症小体激活的负调节剂，并为 TRIM30 在维持炎症反应中的作用提供了新的认识。
