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

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

Author information

1
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.
2
Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
3
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China. Electronic address: qinliu@ecust.edu.cn.
4
Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: gabriel.nunez@umich.edu.

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.

PMID:
26572062
PMCID:
PMC4795157
DOI:
10.1016/j.immuni.2015.10.009
[Indexed for MEDLINE]
Free PMC Article

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