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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.