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首页> 外文期刊>Nature >Cryopyrin activates the inflammasome in response to toxins and ATP.
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Cryopyrin activates the inflammasome in response to toxins and ATP.

机译：隐毒素响应毒素和ATP激活炎性体。

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A crucial part of the innate immune response is the assembly of the inflammasome, a cytosolic complex of proteins that activates caspase-1 to process the proinflammatory cytokines interleukin (IL)-1beta and IL-18. The adaptor protein ASC is essential for inflammasome function, binding directly to caspase-1 (refs 3, 4), but the triggers of this interaction are less clear. ASC also interacts with the adaptor cryopyrin (also known as NALP3 or CIAS1). Activating mutations in cryopyrin are associated with familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease, diseases that are characterized by excessive production of IL-1beta. Here we show that cryopyrin-deficient macrophages cannot activate caspase-1 in response to Toll-like receptor agonists plus ATP, the latter activating the P2X7 receptor to decrease intracellular K+ levels. The release of IL-1beta in response to nigericin, a potassium ionophore, and maitotoxin, a potent marine toxin, was alsofound to be dependent on cryopyrin. In contrast to Asc-/- macrophages, cells deficient in the gene encoding cryopyrin (Cias1-/-) activated caspase-1 and secreted normal levels of IL-1beta and IL-18 when infected with Gram-negative Salmonella typhimurium or Francisella tularensis. Macrophages exposed to Gram-positive Staphylococcus aureus or Listeria monocytogenes, however, required both ASC and cryopyrin to activate caspase-1 and secrete IL-1beta. Therefore, cryopyrin is essential for inflammasome activation in response to signalling pathways triggered specifically by ATP, nigericin, maitotoxin, S. aureus or L. monocytogenes.
机译：先天性免疫应答的关键部分是炎性小体的组装，炎性小体是一种蛋白质的胞质复合物，可激活caspase-1来处理促炎性细胞因子白介素（IL）-1beta和IL-18。衔接蛋白ASC对于炎性体功能至关重要，它直接与caspase-1结合（参考文献3、4），但这种相互作用的触发因素尚不清楚。 ASC还与衔接子冷蛋白（也称为NALP3或CIAS1）相互作用。冷冻蛋白的激活突变与家族性冷性自身炎综合征，Muckle-Wells综合征和新生儿发作的多系统炎性疾病有关，这些疾病的特征在于IL-1beta的过量产生。在这里，我们表明，缺乏冻蛋白的巨噬细胞不能激活caspase-1，以响应Toll样受体激动剂和ATP，后者激活P2X7受体以降低细胞内K +水平。还发现响应于尼古丁（一种钾离子载体）和麦托毒素（一种有效的海洋毒素）的释放，IL-1β的释放依赖于冷冻素。与Asc-/-巨噬细胞相反，当感染了革兰氏阴性鼠伤寒沙门氏菌或土拉弗朗西斯菌时，缺乏编码冷缩蛋白（Cias1-/-）的基因的细胞会激活caspase-1并分泌正常水平的IL-1beta和IL-18。暴露于革兰氏阳性金黄色葡萄球菌或单核细胞增生性李斯特菌的巨噬细胞同时需要ASC和冷冻肽激活caspase-1并分泌IL-1beta。因此，对于响应由ATP，黑霉素，麦托毒素，金黄色葡萄球菌或单核细胞增生李斯特氏菌特异性触发的信号传导途径，冻融蛋白对于炎性体激活至关重要。

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