The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response
The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response
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DOI：
10.1038/ni.2919
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发表时间：
2014-08-01
影响因子：
30.5
通讯作者：
Pelegrin, Pablo
中科院分区：
文献类型：
--
作者：
Baroja-Mazo, Alberto;Martin-Sanchez, Fatima;Pelegrin, Pablo
NLRP 3炎性体的组装激活半胱天冬酶-1并介导无前导细胞因子IL-1 β的加工和释放，从而在炎症反应和多种人类疾病中发挥核心作用。在这里，我们发现，在激活半胱天冬酶-1，寡聚NLRP 3炎性颗粒从巨噬细胞释放。由与cryopyrin-associated periodic syndrome（CAPS）相关的NLRP 3的衔接子ASC或p.D303N突变形式组成的重组寡聚蛋白颗粒在细胞外以及在被周围巨噬细胞吞噬后在细胞内刺激胱天蛋白酶-1的进一步活化。我们在活动性CAPS患者的血清中发现了低聚ASC颗粒，但在其他遗传性自身炎性疾病患者的血清中没有发现。我们的研究结果支持一个模型，其中NLRP 3炎性体，作为一个细胞外的寡聚复合物，放大炎症反应。
Assembly of the NLRP3 inflammasome activates caspase-1 and mediates the processing and release of the leaderless cytokine IL-1 beta and thereby serves a central role in the inflammatory response and in diverse human diseases. Here we found that upon activation of caspase-1, oligomeric NLRP3 inflammasome particles were released from macrophages. Recombinant oligomeric protein particles composed of the adaptor ASC or the p.D303N mutant form of NLRP3 associated with cryopyrin-associated periodic syndromes (CAPS) stimulated further activation of caspase-1 extracellularly, as well as intracellularly after phagocytosis by surrounding macrophages. We found oligomeric ASC particles in the serum of patients with active CAPS but not in that of patients with other inherited autoinflammatory diseases. Our findings support a model whereby the NLRP3 inflammasome, acting as an extracellular oligomeric complex, amplifies the inflammatory response.