Abstract
A crucial part of the innate immune response is the assembly of the inflammasome, a cytosolic complex of proteins that activates caspase-1 to process the proinflammatory cytokines interleukin (IL)-1beta and IL-18. The adaptor protein ASC is essential for inflammasome function, binding directly to caspase-1 (refs 3, 4), but the triggers of this interaction are less clear. ASC also interacts with the adaptor cryopyrin (also known as NALP3 or CIAS1). Activating mutations in cryopyrin are associated with familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease, diseases that are characterized by excessive production of IL-1beta. Here we show that cryopyrin-deficient macrophages cannot activate caspase-1 in response to Toll-like receptor agonists plus ATP, the latter activating the P2X7 receptor to decrease intracellular K+ levels. The release of IL-1beta in response to nigericin, a potassium ionophore, and maitotoxin, a potent marine toxin, was also found to be dependent on cryopyrin. In contrast to Asc-/- macrophages, cells deficient in the gene encoding cryopyrin (Cias1-/-) activated caspase-1 and secreted normal levels of IL-1beta and IL-18 when infected with Gram-negative Salmonella typhimurium or Francisella tularensis. Macrophages exposed to Gram-positive Staphylococcus aureus or Listeria monocytogenes, however, required both ASC and cryopyrin to activate caspase-1 and secrete IL-1beta. Therefore, cryopyrin is essential for inflammasome activation in response to signalling pathways triggered specifically by ATP, nigericin, maitotoxin, S. aureus or L. monocytogenes.
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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Adenosine Triphosphate / metabolism
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Adenosine Triphosphate / pharmacology*
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Animals
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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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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism*
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Enzyme Activation / drug effects
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Inflammation / enzymology
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Inflammation / immunology
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Inflammation / metabolism*
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Interleukin-1 / metabolism
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Listeria monocytogenes / genetics
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Listeria monocytogenes / immunology
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Listeria monocytogenes / physiology
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Macrophages / immunology
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Macrophages / metabolism
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Macrophages / microbiology
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Marine Toxins / pharmacology
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Mice
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Multiprotein Complexes / chemistry
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Multiprotein Complexes / metabolism
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NF-kappa B / metabolism
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nigericin / pharmacology
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Nod2 Signaling Adaptor Protein
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Oxocins / pharmacology
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Signal Transduction / drug effects
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Staphylococcus aureus / immunology
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Staphylococcus aureus / physiology
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Toll-Like Receptors / agonists
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Toll-Like Receptors / immunology
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Toll-Like Receptors / metabolism
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Toxins, Biological / pharmacology*
Substances
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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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Interleukin-1
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Intracellular Signaling Peptides and Proteins
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Marine Toxins
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Multiprotein Complexes
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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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Nod2 Signaling Adaptor Protein
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Nod2 protein, mouse
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Oxocins
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Pycard protein, mouse
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Toll-Like Receptors
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Toxins, Biological
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Adenosine Triphosphate
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maitotoxin
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Extracellular Signal-Regulated MAP Kinases
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Caspase 1
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Nigericin