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

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)-1beta (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-1beta and IL-18 production in response to bacterial RNA and the imidazoquinoline compounds R837 and R848. In contrast, secretion of tumour-necrosis factor-alpha and IL-6, as well as activation of NF-kappaB 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-1beta 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.

• Authors: Thirumala-Devi Kanneganti, Nesrin Ozören, 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
• Journal: Nature (Nature) Vol. 440 Issue 7081 Pg. 233-6 (Mar 09 2006) ISSN: 1476-4687 [Electronic] England
• PMID: 16407888 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Aminoquinolines
• Antiviral Agents
• Apoptosis Regulatory Proteins
• CARD Signaling Adaptor Proteins
• Carrier Proteins
• Cytoskeletal Proteins
• Imidazoles
• Interleukin-1
• Interleukin-18
• Multiprotein Complexes
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• NF-kappa B
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Pycard protein, mouse
• RNA, Bacterial
• Toll-Like Receptors
• Mitogen-Activated Protein Kinases
• Caspase 1
• Imiquimod
• resiquimod

Topics

• Adaptor Proteins, Signal Transducing (deficiency, genetics, metabolism)
• Aminoquinolines (pharmacology)
• Animals
• Antiviral Agents (chemistry, pharmacology)
• Apoptosis Regulatory Proteins
• CARD Signaling Adaptor Proteins
• Carrier Proteins (genetics, metabolism)
• Caspase 1 (metabolism)
• Cells, Cultured
• Cytoskeletal Proteins (deficiency, genetics, metabolism)
• Enzyme Activation (drug effects)
• Female
• Imidazoles (pharmacology)
• Imiquimod
• Inflammation (chemically induced, immunology, metabolism)
• Interleukin-1 (immunology, metabolism)
• Interleukin-18 (immunology, metabolism)
• Legionella pneumophila (genetics, immunology)
• Listeria monocytogenes (genetics, immunology)
• Macrophages, Peritoneal (drug effects, metabolism, microbiology)
• Male
• Mice
• Mitogen-Activated Protein Kinases (metabolism)
• Multiprotein Complexes (chemistry, metabolism)
• Myeloid Differentiation Factor 88
• NF-kappa B (metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein
• RNA, Bacterial (genetics, immunology, pharmacology)
• Toll-Like Receptors (agonists, deficiency, genetics, immunology)