Journal Article

Cryopyrin activates the inflammasome in response to toxins and ATP

McBride, Jacqueline, O'Rourke, Karen, Monack, Denise M., Weiss, David S., Weinrauch, Yvette, Mariathasan, Sanjeev, Roose-Girma, Meron, Dixit, Vishva M., Lee, Wyne P., Newton, Kim

2006

Overview

The first line of defence The inflammasome is a complex of proteins involved in the activation of the innate immune system, an evolutionarily ancient antimicrobial defence found in most multicelled animals. When activated the inflammasome sets in motion a cascade of events that leads to the production of active molecules including interleukins. Three papers in this issue report the identification of endogenous danger signals and bacterial components that activate inflammasomes containing cryopyrin (also known as NALP3). Mariathasan et al . show that cryopyrin activates the inflammasome in response to bacterial toxins and to ATP. Kanneganti et al . show that cryopyrin is activated by bacterial RNA and by the immune response modifiers R837 and R848. And Martinon et al . show that gout-associated uric acid crystals have a similar effect. In sum these results show that cryopyrin has a vital role in host antibacterial defences and may act as a sensor of cellular stress. In addition, this work provides insight into the mechanisms of autoinflammatory disorders in which abnormalities in the innate immune system have been implicated. 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)-1β and IL-18. The adaptor protein ASC is essential for inflammasome function 1 , 2 , 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) 5 , 6 . 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-1β 5 , 7 . Here we show that cryopyrin-deficient macrophages cannot activate caspase-1 in response to Toll-like receptor agonists plus ATP, the latter activating the P2X 7 receptor to decrease intracellular K + levels 8 , 9 . The release of IL-1β 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-1β 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-1β. Therefore, cryopyrin is essential for inflammasome activation in response to signalling pathways triggered specifically by ATP, nigericin, maitotoxin, S. aureus or L. monocytogenes.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Adenosine Triphosphate - metabolism / Adenosine Triphosphate - pharmacology / Animals / Apoptosis Regulatory Proteins / ATP / Bacteriology / Biological and medical sciences / CARD Signaling Adaptor Proteins / Carrier Proteins - genetics / Carrier Proteins - metabolism / Caspase 1 - metabolism / Cytokines / Cytoskeletal Proteins - genetics / Cytoskeletal Proteins - metabolism / Enzyme Activation - drug effects / Extracellular Signal-Regulated MAP Kinases - metabolism / Francisella tularensis / Fundamental and applied biological sciences. Psychology / Humanities and Social Sciences / Immune response / Immune system / Inflammation - enzymology / Inflammation - immunology / Inflammation - metabolism / Interleukin-1 - secretion / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / letter / Listeria monocytogenes / Listeria monocytogenes - genetics / Listeria monocytogenes - immunology / Listeria monocytogenes - physiology / Macrophages - immunology / Macrophages - metabolism / Macrophages - microbiology / Marine Toxins - pharmacology / Mice / Microbiology / multidisciplinary / Multiprotein Complexes - chemistry / Multiprotein Complexes - metabolism / Mutation / NF-kappa B - metabolism / Nigericin - pharmacology / NLR Family, Pyrin Domain-Containing 3 Protein / Nod2 Signaling Adaptor Protein / Oxocins - pharmacology / Pathogenicity, virulence, toxins, bacteriocins, pyrogens, host-bacteria relations, miscellaneous strains / Proteins / Salmonella typhimurium / Science / Science (multidisciplinary) / Signal Transduction - drug effects / Staphylococcus aureus / Staphylococcus aureus - immunology / Staphylococcus aureus - physiology / Toll-Like Receptors - agonists / Toll-Like Receptors - immunology / Toll-Like Receptors - metabolism / Toxins / Toxins, Biological - pharmacology