Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA.
Viral infection induces the production of interleukin (IL)-1beta and IL-18 in macrophages through the activation of caspase-1, but the mechanism by which host cells sense viruses to induce caspase-1 activation is unknown. In this report, we have identified a signaling pathway leading to caspase-1 activation that is induced by double-stranded RNA (dsRNA) and viral infection that is mediated by Cryopyrin/Nalp3. Stimulation of macrophages with dsRNA, viral RNA, or its analog poly(I:C) induced the secretion of IL-1beta and IL-18 in a cryopyrin-dependent manner. Consistently, caspase-1 activation triggered by poly(I:C), dsRNA, and viral RNA was abrogated in macrophages lacking cryopyrin or the adaptor ASC (apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain) but proceeded normally in macrophages deficient in Toll-like receptor 3 or 7. We have also shown that infection with Sendai and influenza viruses activates the cryopyrin inflammasome. Finally, cryopyrin was required for IL-1beta production in response to poly(I:C) in vivo. These results identify a mechanism mediated by cryopyrin and ASC that links dsRNA and viral infection to caspase-1 activation resulting in IL-1beta and IL-18 production.
Kanneganti
Thirumala-Devi
TD
Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Body-Malapel
Mathilde
M
Amer
Amal
A
Park
Jong-Hwan
JH
Whitfield
Joel
J
Franchi
Luigi
L
Taraporewala
Zenobia F
ZF
Miller
David
D
Patton
John T
JT
Inohara
Naohiro
N
Núñez
Gabriel
G
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001854:Bone Marrow Cells / Q000166:cytology; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D020170:Caspase 1 / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000502:physiology; D004789:Enzyme Activation; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008024:Ligands; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009975:Orthomyxoviridae / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000737:chemistry*; D029082:Sendai virus / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D020382:Interleukin-18; D053583:Interleukin-1beta; D008024:Ligands; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D012330:RNA, Double-Stranded; D020170:Caspase 1