Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1

Immunity. 2006 Mar;24(3):317-27. doi: 10.1016/j.immuni.2006.02.004.


Mutations in the NALP3/CIAS1/cryopyrin gene are linked to three autoinflammatory disorders: Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and chronic infantile neurologic cutaneous and articular syndrome. NALP3, with the adaptor molecule ASC, has been proposed to form a caspase-1-activating "inflammasome," a complex with pro-IL1beta-processing activity. Here, we demonstrate the effect of NALP3 deficiency on caspase-1 function. NALP3 was essential for the ATP-driven activation of caspase-1 in lipopolysaccharide-stimulated macrophages and for the efficient secretion of the caspase-1-dependent cytokines IL-1alpha, IL-1beta, and IL-18. IL-1beta has been shown to play a key role in contact hypersensitivity; we show that ASC- and NALP3-deficient mice also demonstrate an impaired contact hypersensitivity response to the hapten trinitrophenylchloride. NALP3, however, was not required for caspase-1 activation by Salmonella typhimurium, and NALP3 deficiency only partially protects mice from the lethal effects of endotoxin. These data suggest that NALP3 plays a specific role in the caspase-1 activation pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / pharmacology
  • Animals
  • Apoptosis Regulatory Proteins
  • Autoimmune Diseases / etiology
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / physiology*
  • Caspase 1 / physiology*
  • Cytoskeletal Proteins / physiology
  • Enzyme Activation
  • Immunity, Innate*
  • Interleukin-1 / physiology
  • Lipopolysaccharides / pharmacology
  • Macrophages / immunology
  • Mice
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • RNA, Messenger / analysis
  • Salmonella typhimurium / immunology
  • Shock, Septic / etiology
  • Toll-Like Receptors / physiology


  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • Interleukin-1
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Pycard protein, mouse
  • RNA, Messenger
  • Toll-Like Receptors
  • Adenosine Triphosphate
  • Caspase 1