title: Caspase-11 Requires the Pannexin-1 Channel and the Purinergic P2X7 Pore to Mediate Pyroptosis and Endotoxic Shock.
abstract: 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.
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Dahai
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Muñoz-Planillo
authors.affiliation: State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China. Electronic address: qinliu@ecust.edu.cn.
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: gabriel.nunez@umich.edu.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D020169:Caspases / Q000378:metabolism*; D053471:Caspases, Initiator; D002460:Cell Line; D017630:Connexins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D000069292:Pyroptosis / Q000187:drug effects / Q000502:physiology*; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D012772:Shock, Septic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051196:Toll-Like Receptor 3 / Q000378:metabolism
chemical_list: D017630:Connexins; D058847:Inflammasomes; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; C503631:Panx1 protein, mouse; D058486:Receptors, Purinergic P2X7; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D000255:Adenosine Triphosphate; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator