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

Immunity. 2015 Nov 17;43(5):923-32. doi: 10.1016/j.immuni.2015.10.009. Epub 2015 Nov 10.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Caspases / metabolism*
  • Cell Line
  • Connexins / metabolism*
  • HEK293 Cells
  • Humans
  • Inflammasomes / drug effects
  • Inflammasomes / metabolism
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / metabolism*
  • Pyroptosis / drug effects
  • Pyroptosis / physiology*
  • Receptors, Purinergic P2X7 / metabolism*
  • Shock, Septic / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Toll-Like Receptor 3 / metabolism

Substances

  • Connexins
  • Inflammasomes
  • Lipopolysaccharides
  • Nerve Tissue Proteins
  • Panx1 protein, mouse
  • Receptors, Purinergic P2X7
  • TLR3 protein, mouse
  • Toll-Like Receptor 3
  • Adenosine Triphosphate
  • Casp4 protein, mouse
  • Caspases