Cryopyrin: A Specific Activator of the Inflammasome

Abstract

Three articles (Martinon et al ., Kanneganti et al ., and Mariathasan et al .) this week highlight the importance of cryopyrin, which is a member of the NOD-LRR family of nucleotide-binding domain and leucin-rich repeat proteins that serve as pattern recognition proteins. Cryopyrin (also known as CIAS1 and NALP3) is part of the inflammasome complex that also includes apoptosis-associated speck-like protein (ASC) and caspase-1 and that is responsible for processing caspase-1 to its active form. Caspase-1 cleaves the precursors of interleukin (IL)-1β and IL-18, thereby activating these proinflammatory cytokines and promoting their secretion. Each group generated mice in which the gene-encoding cryopyrin, Cias1 , was knocked out and then investigated caspase-1 activation and IL-1β secretion in response to various inflammatory agents. Martinon et al . showed that cryopyrin was required for caspase-1 activation and IL-1β secretion in response to the two types of uric acid crystals responsible for gout and pseudogout. Kanneganti et al . showed that cryopyrin was required for caspase-1 activation and IL-1β secretion in response to bacterial RNA and the structurally related molecules imiquimod and resiquimod. Kanneganti et al . also reported that cryopyrin deficiency did not alter IL-1β secretion in response to the Toll-like receptor (TLR) agonists, lipopolysaccharide (LPS), lipid A, lipoteichoic acid, or two synthetic lipopeptides (Pam 2 CGDPKHPHSF and Pam 3 CSK 4 ). Mariathasan et al . showed that cryopyrin was required for ATP-induced IL-1β secretion in macrophages that had been previously exposed to LPS, Pam 3 CSK 4 , or heat-killed Listeria monocytogenes . ATP can trigger a decrease in intracellular K + concentration, and K + ionophore-triggered IL-1β secretion from TLR-primed macrophages required cryopyrin. Cryopyrin was also essential for IL-1β secretion in response to the Gram-positive bacteria Staphylococcus aureus or L. monocytogenes , but was not required for secretion in response to the Gram-negative bacteria Salmonella typhimurium or Francisella tularensis . Cias1 -/- mice were protected from endotoxic shock caused by injection of LPS. Thus, cryopyrin appears to serve as an activator of the inflammasome in response to specific toxins, endogenous danger signals (elevated ATP, uric acid crystals), or microbial pathogens. These results provide a mechanistic basis for the autoinflammatory diseases associated with mutations in the human CIAS1 gene. F. Martinon, V. Pétrilli, A. Mayor, A. Tardivel, J. Tschopp, Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440 , 237-241 (2006). [PubMed] T.-D. Kanneganti, N. Özören, M. Body-Malapel, A. Amer, J.-H. Park, L. Franchi, J. Whitfield, W. Barchet, M. Colonna, P. Vandenabeele, J. Bertin, A. Coyle, E. P. Grant, S. Akira, G. Núñez, Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440 , 233-236 (2006). [PubMed] S. Mariathasan, D. S. Weiss, K. Newton, J. McBride, K. O'Rourke, M. Roose-Girma, W. P. Lee, Y. Weinrauch, D. M. Monack, V. M. Dixit, Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440 , 228-232 (2006). [PubMed]