| | |  | | | | Record from Web of Science® | | | | | | |
| Cryopyrin activates the inflammasome in response to toxins and ATP |
|
|
| Author(s): Mariathasan S, Weiss DS, Newton K, McBride J, O'Rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monack DM, Dixit VM |
| Source: NATURE Volume: 440 Issue: 7081 Pages: 228-232 Published: MAR 9 2006 |
| Times Cited: 368 References: 25 |
| 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)-1 beta 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-1 beta(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-1 beta 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-1 beta 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-1 beta. Therefore, cryopyrin is essential for inflammasome activation in response to signalling pathways triggered specifically by ATP, nigericin, maitotoxin, S. aureus or L. monocytogenes. |
| Document Type: Article |
| Language: English |
| Reprint Address: Dixit, VM (reprint author), Genentech Inc, Dept Mol Oncol, 1 DNA Way, San Francisco, CA 94080 USA |
Addresses:
1. Genentech Inc, Dept Mol Oncol, San Francisco, CA 94080 USA
2. Genentech Inc, Dept Physiol, San Francisco, CA 94080 USA
3. Genentech Inc, Dept Immunol, San Francisco, CA 94080 USA
4. Stanford Univ, Sch Med, Dept Microbiol, Stanford, CA 94305 USA
5. Stanford Univ, Sch Med, Dept Immunol, Stanford, CA 94305 USA
6. NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA |
| Publisher: NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND |
| Subject Category: Multidisciplinary Sciences |
| IDS Number: 019MC |
| ISSN: 0028-0836 |
| DOI: 10.1038/nature04515 |
|
| | | | | | | | | Record from Web of Science® | | | | | | | | | |