Neutrophil-specific gain-of-function mutations in Nlrp3 promote development of cryopyrin-associated periodic syndrome

J Exp Med. 2021 Oct 4;218(10):e20201466. doi: 10.1084/jem.20201466. Epub 2021 Sep 3.


Gain-of-function mutations in NLRP3 are responsible for a spectrum of autoinflammatory diseases collectively referred to as "cryopyrin-associated periodic syndromes" (CAPS). Treatment of CAPS patients with IL-1-targeted therapies is effective, confirming a central pathogenic role for IL-1β. However, the specific myeloid cell population(s) exhibiting inflammasome activity and sustained IL-1β production in CAPS remains elusive. Previous reports suggested an important role for mast cells (MCs) in this process. Here, we report that, in mice, gain-of-function mutations in Nlrp3 restricted to neutrophils, and to a lesser extent macrophages/dendritic cells, but not MCs, are sufficient to trigger severe CAPS. Furthermore, in patients with clinically established CAPS, we show that skin-infiltrating neutrophils represent a substantial biological source of IL-1β. Together, our data indicate that neutrophils, rather than MCs, can represent the main cellular drivers of CAPS pathology.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Aged, 80 and over
  • Animals
  • Cryopyrin-Associated Periodic Syndromes / genetics*
  • Cryopyrin-Associated Periodic Syndromes / pathology*
  • Female
  • Gain of Function Mutation
  • Humans
  • Interleukin-1beta / metabolism
  • Male
  • Mast Cells / pathology
  • Mice, Transgenic
  • Middle Aged
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Neutrophils* / pathology
  • Neutrophils* / physiology


  • IL1B protein, human
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nlrp3 protein, mouse