文献类型：期刊文献

英文题名：Caspase-11 Requires the Pannexin-1 Channel and the Purinergic P2X7 Pore to Mediate Pyroptosis and Endotoxic Shock

作者：Yang, Dahai[1,2,3];He, Yuan[1,2];Munoz-Planillo, Raul[1,2];Liu, Qin[3];Nunez, Gabriel[1,2]

机构：[1]Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA;[2]Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA;[3]E China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China

年份：2015

卷号：43

期号：5

起止页码：923

外文期刊名：IMMUNITY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000366846000013)】；

基金：We thank Junying Yuan for sharing Casp11-/- mice, Vishva Dixit (Genentech) for sharing Panx1-/- and Aim2-/- mice, Amal Amer for providing caspase-11 plasmids, and Melody Zeng, Grace Chen, and Jessica Werner for critical reading of the manuscript. We also thank members of the Nunez laboratory for discussions and technical assistance, Lisa Burmeister for mouse husbandry, and Joel Whitfield from the University of Michigan Immunology Core for performing ELISA assays. D.Y. was supported by the State Scholarship Fund from China Scholarship Council (No. 201306740018). This work was supported by grants R01AI063331 and R01DK091191 from the National Institutes of Health to G.N.

语种：英文

摘要：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 followed up by ATP release, which in turn activated the purinergic P2X7 receptor to mediate cytotoxicity. In the absence of P2X7 or pannexin-1, pyroptosis induced by cytosolic 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.