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- Title
Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3.
- Authors
Kanneganti, Thirumala-Devi; Özören, Nesrin; Body-Malapel, Mathilde; Amer, Amal; Park, Jong-Hwan; Franchi, Luigi; Whitfield, Joel; Barchet, Winfried; Colonna, Marco; Vandenabeele, Peter; Bertin, John; Coyle, Anthony; Grant, Ethan P.; Akira, Shizuo; Núñez, Gabriel
- Abstract
Missense mutations in the CIAS1 gene cause three autoinflammatory disorders: familial cold autoinflammatory syndrome, Muckle–Wells syndrome and neonatal-onset multiple-system inflammatory disease. 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 pathways. 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.
- Subjects
GENETIC mutation; IMMUNE system; IMMUNE response; TUMOR necrosis factors; PROTEIN kinases; DRUG resistance in microorganisms; ANTIVIRAL agents
- Publication
Nature, 2006, Vol 440, Issue 7081, p233
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature04517