Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3

Thirumala Devi Kanneganti, Nesrin Özören, Mathilde Body-Malapel, Amal Amer, Jong Hwan Park, Luigi Franchi, Joel Whitfield, Winfried Barchet, Marco Colonna, Peter Vandenabeele, John Bertin, Anthony Coyle, Ethan P. Grant, Shizuo Akira, Gabriel Núñez

Research output: Contribution to journalArticlepeer-review

871 Scopus citations

Abstract

Missense mutations in the CIAS1 gene cause three autoinflammatory disorders: familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multiple-system inflammatory disease1. Cryopyrin (also called Nalp3), the product of CIAS1, is a member of the NOD-LRR protein family that has been linked to the activation of intracellular host defence signalling pathways2,3. Cryopyrin forms a multi-protein complex termed 'the inflammasome', which contains the apoptosis-associated speck-like protein (ASC) and caspase-1, and promotes caspase-1 activation and processing of pro-interleukin (IL)-1β (ref. 4). Here we show the effect of cryopyrin deficiency on inflammasome function and immune responses. Cryopyrin and ASC are essential for caspase-1 activation and IL-1β and IL-18 production in response to bacterial RNA and the imidazoquinoline compounds R837 and R848. In contrast, secretion of tumour-necrosis factor-α and IL-6, as well as activation of NF-κB and mitogen-activated protein kinases (MAPKs) were unaffected by cryopyrin deficiency. Furthermore, we show that Toll-like receptors and cryopyrin control the secretion of IL-1β and IL-18 through different intracellular pathways. These results reveal a critical role for cryopyrin in host defence through bacterial RNA-mediated activation of caspase-1, and provide insights regarding the pathogenesis of autoinflammatory syndromes.

Original languageEnglish
Pages (from-to)233-236
Number of pages4
JournalNature
Volume440
Issue number7081
DOIs
StatePublished - Mar 9 2006

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