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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / deficiency
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Aminoquinolines / pharmacology
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Animals
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology*
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Apoptosis Regulatory Proteins
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CARD Signaling Adaptor Proteins
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Caspase 1 / metabolism*
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Cells, Cultured
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Cytoskeletal Proteins / deficiency
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism
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Enzyme Activation / drug effects
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Female
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Imidazoles / pharmacology
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Imiquimod
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Inflammation / chemically induced
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Inflammation / immunology
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Inflammation / metabolism
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Interleukin-1 / immunology
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Interleukin-1 / metabolism
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Interleukin-18 / immunology
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Interleukin-18 / metabolism
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Legionella pneumophila / genetics
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Legionella pneumophila / immunology
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Listeria monocytogenes / genetics
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Listeria monocytogenes / immunology
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Macrophages, Peritoneal / drug effects
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Macrophages, Peritoneal / metabolism
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Macrophages, Peritoneal / microbiology
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Male
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Mice
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Mitogen-Activated Protein Kinases / metabolism
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Multiprotein Complexes / chemistry
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Multiprotein Complexes / metabolism
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Myeloid Differentiation Factor 88
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NF-kappa B / metabolism
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NLR Family, Pyrin Domain-Containing 3 Protein
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RNA, Bacterial / genetics
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RNA, Bacterial / immunology
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RNA, Bacterial / pharmacology*
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Toll-Like Receptors / agonists
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Toll-Like Receptors / deficiency
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Toll-Like Receptors / genetics
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Toll-Like Receptors / immunology
Substances
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Adaptor Proteins, Signal Transducing
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Aminoquinolines
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Antiviral Agents
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Apoptosis Regulatory Proteins
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CARD Signaling Adaptor Proteins
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Carrier Proteins
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Cytoskeletal Proteins
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Imidazoles
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Interleukin-1
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Interleukin-18
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Multiprotein Complexes
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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NF-kappa B
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Pycard protein, mouse
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RNA, Bacterial
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Toll-Like Receptors
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Mitogen-Activated Protein Kinases
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Caspase 1
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Imiquimod
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resiquimod