Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies

J Clin Invest. 2013 Nov;123(11):4695-705. doi: 10.1172/JCI71543.


The inflammasome is a cytoplasmic multiprotein complex that promotes proinflammatory cytokine maturation in response to host- and pathogen-derived signals. Missense mutations in cryopyrin (NLRP3) result in a hyperactive inflammasome that drives overproduction of the proinflammatory cytokines IL-1β and IL-18, leading to the cryopyrin-associated periodic syndromes (CAPS) disease spectrum. Mouse lines harboring CAPS-associated mutations in Nlrp3 have elevated levels of IL-1β and IL-18 and closely mimic human disease. To examine the role of inflammasome-driven IL-18 in murine CAPS, we bred Nlrp3 mutations onto an Il18r-null background. Deletion of Il18r resulted in partial phenotypic rescue that abolished skin and visceral disease in young mice and normalized serum cytokines to a greater extent than breeding to Il1r-null mice. Significant systemic inflammation developed in aging Nlrp3 mutant Il18r-null mice, indicating that IL-1 and IL-18 drive pathology at different stages of the disease process. Ongoing inflammation in double-cytokine knockout CAPS mice implicated a role for caspase-1-mediated pyroptosis and confirmed that CAPS is inflammasome dependent. Our results have important implications for patients with CAPS and residual disease, emphasizing the need to explore other NLRP3-mediated pathways and the potential for inflammasome-targeted therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / pathology
  • Carrier Proteins / genetics*
  • Caspase 1 / deficiency
  • Caspase 1 / genetics
  • Caspase 1 / metabolism
  • Cell Death
  • Cryopyrin-Associated Periodic Syndromes / genetics*
  • Cryopyrin-Associated Periodic Syndromes / immunology*
  • Cryopyrin-Associated Periodic Syndromes / pathology
  • Disease Models, Animal
  • Humans
  • Inflammasomes / genetics*
  • Inflammasomes / immunology*
  • Interleukin-18 / biosynthesis*
  • Interleukin-18 / blood
  • Interleukin-1beta / biosynthesis*
  • Interleukin-1beta / blood
  • Liver / immunology
  • Liver / pathology
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mutant Proteins / genetics
  • Mutation
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Receptors, Interleukin-1 / deficiency
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-18 / deficiency
  • Receptors, Interleukin-18 / genetics
  • Skin / immunology
  • Skin / pathology


  • Carrier Proteins
  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • Mutant Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Receptors, Interleukin-1
  • Receptors, Interleukin-18
  • Caspase 1