Pannexin-1-mediated Recognition of Bacterial Molecules Activates the Cryopyrin Inflammasome Independent of Toll-like Receptor Signaling

Immunity. 2007 Apr;26(4):433-43. doi: 10.1016/j.immuni.2007.03.008. Epub 2007 Apr 12.

Abstract

Cryopyrin is essential for caspase-1 activation triggered by Toll-like receptor (TLR) ligands in the presence of adenosine triphosphate (ATP). However, the events linking bacterial products and ATP to cryopyrin remain unclear. Here we demonstrate that cryopyrin-mediated caspase-1 activation proceeds independently of TLR signaling, thus dissociating caspase-1 activation and IL-1beta secretion. Instead, caspase-1 activation required pannexin-1, a hemichannel protein that interacts with the P2X(7) receptor. Direct cytosolic delivery of multiple bacterial products including lipopolysaccharide, but not flagellin, induced caspase-1 activation via cryopyrin in the absence of pannexin-1 activity or ATP stimulation. However, unlike Ipaf-dependent caspase-1 activation, stimulation of the pannexin-1-cryopyrin pathway by several intracellular bacteria was independent of a functional bacterial type III secretion system. These results provide evidence for cytosolic delivery and sensing of bacterial molecules as a unifying model for caspase-1 activation and position pannexin-1 as a mechanistic link between bacterial stimuli and the cryopyrin inflammasome.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Bacteria / immunology*
  • Calcium-Binding Proteins / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Caspase 1 / metabolism
  • Connexins
  • Cytosol / immunology
  • Cytosol / microbiology
  • Enzyme Activation
  • Inflammation / immunology
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides / immunology*
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Mutant Strains
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Receptors, Purinergic P2 / metabolism
  • Receptors, Purinergic P2X7
  • Toll-Like Receptors / immunology

Substances

  • Apoptosis Regulatory Proteins
  • Calcium-Binding Proteins
  • Carrier Proteins
  • Connexins
  • Interleukin-1beta
  • Ipaf protein, mouse
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nerve Tissue Proteins
  • Nlrp3 protein, mouse
  • P2rx7 protein, mouse
  • Panx1 protein, mouse
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2X7
  • Toll-Like Receptors
  • Caspase 1