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

Abstract

SUMMARY 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 and ATP release, which in turn activated the purinergic P2X7 receptor to mediate cytotoxicity. In the absence of P2X7 or pannexin-1, pyroptosis induced by LPS transfection or treatment with cholera toxin B and 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.

Inflammasomes and its importance in viral infections

“…Furthermore, pyroptosis, which is associated with a highly inflammatory state induced by intracellular pathogens, has been reported to possibly contribute to an inflammatory syndrome in vivo [115]. In the non-canonical inflammasome pathway, it has been demonstrated that upon intracellular lipopolysaccharide (LPS) stimulation, caspase-11 cleaves the pannexin-1 channel resulting in the release of ATP, which in turn activates P2X7 to induce cytotoxicity and pyroptosis [116,117]. Recent findings have suggested that the presence of cytosolic LPS dramatically decreases the threshold concentration of ATP necessary to drive the opening of the P2X7 channel, which allows the release of proinflammatory cytokines such as IL-1b.…”

“…This further leads to P2X7 forming a receptor pore, allowing it to respond to the nanomolar concentration of released ATP. During the course of pyroptosis, ATP mostly works as an autocrine signal that targets the cells primed with hypersensitive P2X7 channels (such as those in which cytosolic LPS were detected) [116]. In addition, pannexin-1 was suggested to be necessary for mediating IL-1b release due to caspase-11 activation triggered by pannexin-1-mediated K ?…”

POM-1 inhibits P2 receptors and exhibits anti-inflammatory effects in macrophages

“…Recently, Yang and collaborators presented data indicating that pannexin-1 and P2X7R are required for susceptibility to endotoxic shock in mice induced via the non-canonical inflammasome pathway [74]. However, how P2X7R regulates the caspase-11 activation and what the role of pannexin-1 is in this process is not known yet.…”

Gasdermins pore cell membrane to pyroptosis

“…Furthermore, although residues participating in oligomerization and membrane insertion were proposed, the structural basis of gasdermin-N pore formation remains to be fully elucidated. In addition to gasdermin, a cytotoxicity mediated by pannexin1-P2X7 was reported recently (Yang et al, 2015). Caspase-11-dependent cleavage of the pannexin-1 allows the release of ATP which further activates P2X7 to mediate pyroptosis.…”

“…A crucial substrate of inflammatory caspases, gasdermin D (GSDMD), was independently identified by several groups in 2015 (He et al, 2015;Kayagaki et al, 2015;Shi et al, 2015). According to their results, GSDMD is cleaved by the activated caspases-1/4/5/11 between its N-terminal and C-terminal domains.…”