Caspase-11 Requires the Pannexin-1 Channel and the Purinergic P2X7 Pore to Mediate Pyroptosis and Endotoxic Shock.
Caspase-11 Requires the Pannexin-1 Channel and the Purinergic P2X7 Pore to Mediate Pyroptosis and Endotoxic Shock.
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DOI：
10.1016/j.immuni.2015.10.009
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发表时间：
2015-11-17
期刊：
影响因子：
32.4
通讯作者：
Núñez G
中科院分区：
文献类型：
--
作者：
Yang D;He Y;Muñoz-Planillo R;Liu Q;Núñez G
细胞内脂多糖 (LPS) 诱导的非典型炎症小体会导致 caspase-11 依赖性焦亡，这对于诱导小鼠内毒素休克至关重要。然而，caspase-11 下游的信号通路尚不清楚。我们发现胞质 LPS 刺激诱导 caspase-11 依赖性 pannexin-1 通道裂解和 ATP 释放，进而激活嘌呤能 P2X7 受体以介导细胞毒性。在缺乏 P2X7 或 pannexin-1 的情况下，由 LPS 转染或用霍乱毒素 B 和 LPS 处理诱导的细胞焦亡被消除。 pannexin-1 的裂解需要 caspase-11 的催化活性，并且对于 ATP 释放和 P2X7 介导的细胞焦亡至关重要。用 LPS 或 Toll 样受体 3 (TLR3) 激动剂启动体内 caspase-11 通路会导致二次 LPS 攻击后野生型小鼠的高死亡率，但在 Casp11−/−、Panx1−/− 或 P2x7−/− 小鼠中则不然。这些结果揭示了 caspase-11 下游的 pannexin-1 和 P2X7 对于细胞焦亡和非典型炎症小体诱导的脓毒症易感性发挥着关键作用。
The noncanonical inflammasome induced by intracellular lipopolysaccharide (LPS) leads to caspase-11-dependent pyroptosis which is critical for induction of endotoxic shock in mice. However, the signaling pathway downstream of caspase-11 is unknown. We found that cytosolic LPS stimulation induced caspase-11-dependent cleavage of the pannexin-1 channel and ATP release, which in turn activated the purinergic P2X7 receptor to mediate cytotoxicity. In the absence of P2X7 or pannexin-1, pyroptosis induced by LPS transfection or treatment with cholera toxin B and LPS was abrogated. Cleavage of pannexin-1 required the catalytic activity of caspase-11 and was essential for ATP release and P2X7-mediated pyroptosis. Priming the caspase-11 pathway in vivo with LPS or toll-like receptor-3 (TLR3) agonist resulted in high mortality in wild-type mice after secondary LPS challenge, but not in Casp11−/−, Panx1−/− or P2x7−/− mice. These results reveal a critical role for pannexin-1 and P2X7 downstream of caspase-11 for pyroptosis and susceptibility to sepsis induced by the noncanonical inflammasome.