TY - JOUR
T1 - Pannexin-1-Mediated Recognition of Bacterial Molecules Activates the Cryopyrin Inflammasome Independent of Toll-like Receptor Signaling
AU - Kanneganti, Thirumala Devi
AU - Lamkanfi, Mohamed
AU - Kim, Yun Gi
AU - Chen, Grace
AU - Park, Jong Hwan
AU - Franchi, Luigi
AU - Vandenabeele, Peter
AU - Núñez, Gabriel
N1 - Funding Information:
We thank A. Coyle, E. Grant, and J. Bertin (Millennium Pharmaceuticals) and S. Akira (Osaka University) for generous supply of mutant mice and J. Whitfield from the Cellular Immunology Core Facility of the University of Michigan Cancer Center for technical support. T.-D.K. was supported by Training Grant 5/T32/HL007517 from National Institutes of Health. Research at P.V.'s lab is supported by grants from IAP6/18, GOA 12.0505.02, FWO 2G.0218.06, Belgian Foundation against Cancer SCIE2003-48. This work was supported by National Institutes of Health Grants AI063331 and A/064748 to G.N. The authors declare that they have no competing financial interests.
PY - 2007/4/27
Y1 - 2007/4/27
N2 - 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-1β secretion. Instead, caspase-1 activation required pannexin-1, a hemichannel protein that interacts with the P2X7 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.
AB - 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-1β secretion. Instead, caspase-1 activation required pannexin-1, a hemichannel protein that interacts with the P2X7 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.
KW - CELLIMMUNO
KW - MOLIMMUNO
KW - SIGNALING
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U2 - 10.1016/j.immuni.2007.03.008
DO - 10.1016/j.immuni.2007.03.008
M3 - Article
C2 - 17433728
AN - SCOPUS:34247118826
VL - 26
SP - 433
EP - 443
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 4
ER -