Extracellular Ca2+ is a danger signal activating the NLRP3 inflammasome through G protein-coupled calcium sensing receptors.
Extracellular Ca2+ is a danger signal activating the NLRP3 inflammasome through G protein-coupled calcium sensing receptors.
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DOI：
10.1038/ncomms2339
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发表时间：
2012
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
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NLRP 3炎性体的激活使单核细胞和巨噬细胞能够在炎症反应期间释放高水平的白细胞介素-1 β。细胞外钙浓度可在感染、炎症或细胞活化部位增加。在这里，我们表明，增加细胞外钙激活NLRP 3炎症体通过刺激G蛋白偶联钙敏感受体。激活是由钙敏感受体和GPRC 6A通过磷脂酰肌醇/Ca 2+途径发出的信号介导的。细胞内钙浓度的增加触发炎性小体组装和半胱天冬酶-1活化。我们确定坏死细胞是触发这种激活的过量细胞外钙的一个来源。在体内，钙浓度增加可以放大角叉菜胶诱导的足垫肿胀小鼠模型中的炎症反应，而这种作用在GPRC 6A −/−小鼠中受到抑制。我们的研究结果表明，G蛋白偶联受体可以激活炎性小体，并表明细胞外钙离子的增加具有危险信号和炎症放大器的作用。 细胞外钙的水平可以在感染和炎症部位增加;然而，其生理意义尚不清楚。这项工作表明，细胞外钙作为一种危险信号，通过两个G蛋白偶联受体触发NLRP 3炎性体。
Activation of the NLRP3 inflammasome enables monocytes and macrophages to release high levels of interleukin-1β during inflammatory responses. Concentrations of extracellular calcium can increase at sites of infection, inflammation or cell activation. Here we show that increased extracellular calcium activates the NLRP3 inflammasome via stimulation of G protein-coupled calcium sensing receptors. Activation is mediated by signalling through the calcium-sensing receptor and GPRC6A via the phosphatidyl inositol/Ca2+ pathway. The resulting increase in the intracellular calcium concentration triggers inflammasome assembly and Caspase-1 activation. We identified necrotic cells as one source for excess extracellular calcium triggering this activation. In vivo, increased calcium concentrations can amplify the inflammatory response in the mouse model of carrageenan-induced footpad swelling, and this effect was inhibited in GPRC6A−/− mice. Our results demonstrate that G-protein-coupled receptors can activate the inflammasome, and indicate that increased extracellular calcium has a role as a danger signal and amplifier of inflammation. Levels of extracellular calcium can increase at sites of infection and inflammation; however, the physiological significance of this has been unclear. This work shows that extracellular calcium acts as a danger signal, triggering the NLRP3 inflammasome via two G protein-coupled receptors.
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