1. Molecular Oncology Department,
2. Physiology Department,
3. Immunology Department, Genentech Inc, 1 DNA Way, South San Francisco, California 94080, USA
4. Departments of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA
5. Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA

Correspondence to: Vishva M. Dixit¹ Correspondence and requests for materials should be addressed to V.M.D. (Email: dixit@gene.com).

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 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^{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 P2X₇ receptor to decrease intracellular K⁺ levels^{8, 9}. The release of IL-1 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 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. Therefore, cryopyrin is essential for inflammasome activation in response to signalling pathways triggered specifically by ATP, nigericin, maitotoxin, S. aureus or L. monocytogenes.

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