Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/cryopyrin/NLRP3 and ASC

Cell Host Microbe. 2007 Sep 13;2(3):147-59. doi: 10.1016/j.chom.2007.07.009.


Cryopyrin (CIAS1, NLRP3) and ASC are components of the inflammasome, a multiprotein complex required for caspase-1 activation and cytokine IL-1beta production. CIAS1 mutations underlie autoinflammation characterized by excessive IL-1beta secretion. Disease-associated cryopyrin also causes a program of necrosis-like cell death in macrophages, the mechanistic details of which are unknown. We find that patient monocytes carrying disease-associated CIAS1 mutations exhibit excessive necrosis-like death by a process dependent on ASC and cathepsin B, resulting in spillage of the proinflammatory mediator HMGB1. Shigella flexneri infection also causes cryopyrin-dependent macrophage necrosis with features similar to the death caused by mutant CIAS1. This necrotic death is independent of caspase-1 and IL-1beta, and thus independent of the inflammasome. Furthermore, necrosis of primary macrophages requires the presence of Shigella virulence genes. While similar proteins mediate pathogen-induced cell death in plants, this report identifies cryopyrin as an important host regulator of programmed pathogen-induced necrosis in animals, a process we term pyronecrosis.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Animals
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Caspase 1 / immunology
  • Cathepsins / physiology
  • Cell Death / immunology*
  • Cell Line
  • Cells, Cultured
  • Cytoskeletal Proteins / immunology*
  • Female
  • HMGB1 Protein / metabolism
  • Humans
  • Interleukin-1beta / immunology
  • Macrophages / microbiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Shigella flexneri / genetics
  • Shigella flexneri / pathogenicity*
  • Virulence Factors / genetics


  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • HMGB1 Protein
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • PYCARD protein, human
  • Virulence Factors
  • Cathepsins
  • Caspase 1