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Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage

Jae Jin Chae1, Hirsh D Komarow, Jun Cheng

  • 1Inflammatory Biology Section, Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892, USA. chaej@exchange.nih.gov

Molecular Cell
|April 2, 2003
PubMed

Insights

Familial Mediterranean fever (FMF) is an inherited inflammatory disorder. Our study reveals pyrin

Area of Science:

  • Immunology
  • Genetics
  • Molecular Biology

Background:

  • Familial Mediterranean fever (FMF) is an inherited autoinflammatory disorder.
  • FMF is associated with mutations in the pyrin gene.
  • Pyrin's precise role in innate immunity is not fully understood.

Purpose of the Study:

  • To investigate the physiological function of pyrin in innate immunity.
  • To elucidate the molecular mechanisms underlying pyrin's role in inflammation.

Main Methods:

  • Generation of mice expressing a truncated pyrin molecule, mimicking FMF-associated mutations.
  • Stimulation of mutant mice and their macrophages with bacterial lipopolysaccharide (LPS).
  • Analysis of inflammatory responses, including caspase-1 activation, IL-1beta production, and apoptosis.

Main Results:

  • Homozygous mutant mice exhibited heightened fever and mortality upon LPS challenge.
  • Macrophages from mutant mice showed increased caspase-1 activation and mature IL-1beta secretion.
  • Full-length pyrin inhibited caspase-1 binding to ASC in vitro.
  • Apoptosis was impaired in macrophages from pyrin-truncation mice via an IL-1-independent pathway.

Conclusions:

  • Pyrin plays a crucial role in regulating innate immune responses, potentially by interacting with ASC.
  • Pyrin's function is critical for controlling inflammatory signaling pathways.
  • These findings provide a biological basis for FMF pathogenesis and the selection of specific pyrin variants.

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