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Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages
Published on: May 21, 2018
Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1β activation and severe
Jae Jin Chae1, Young-Hun Cho, Geun-Shik Lee
1Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. chaej@mail.nih.gov
Abstract:
Missense mutations in the C-terminal B30.2 domain of pyrin cause familial Mediterranean fever (FMF), the most common Mendelian autoinflammatory disease. However, it remains controversial as to whether FMF is due to the loss of an inhibitor of inflammation or to the activity of a proinflammatory molecule. We generated both pyrin-deficient mice and "knockin" mice harboring mutant human B30.2 domains. Homozygous knockin, but not pyrin-deficient, mice exhibited spontaneous bone marrow-dependent inflammation similar to but more severe than human FMF. Caspase-1 was constitutively activated in knockin macrophages and active IL-1β was secreted when stimulated with lipopolysaccharide alone, which is also observed in FMF patients. The inflammatory phenotype of knockin mice was completely ablated by crossing with IL-1 receptor-deficient or adaptor molecule ASC-deficient mice, but not NLRP3-deficient mice. Thus, our data provide evidence for an ASC-dependent NLRP3-independent inflammasome in which gain-of-function pyrin mutations cause autoinflammatory disease.
Insights
Gain-of-function mutations in pyrin cause familial Mediterranean fever (FMF) by activating an ASC-dependent inflammasome. Pyrin deficiency did not cause inflammation, supporting a gain-of-function mechanism in this autoinflammatory disease.
Area of Science:
- Genetics and Molecular Biology
- Immunology
- Disease Mechanisms
Background:
- Familial Mediterranean fever (FMF) is a common autoinflammatory disease caused by pyrin mutations.
- The exact mechanism of FMF pathogenesis, whether loss-of-inhibition or gain-of-function, remains debated.
Purpose of the Study:
- To elucidate the pathogenic mechanism of pyrin mutations in FMF.
- To investigate the role of pyrin in inflammasome activation and inflammation.
Main Methods:
- Generation of pyrin-deficient and pyrin mutant "knockin" mouse models.
- Analysis of inflammatory phenotypes, including bone marrow-dependent inflammation and IL-1β secretion.
- Genetic ablation of IL-1 receptor, ASC, and NLRP3 to assess inflammasome components.
Main Results:
- Pyrin knockin mice, but not deficient mice, exhibited severe spontaneous inflammation.
- Constitutive caspase-1 activation and IL-1β secretion were observed in knockin macrophages.
- Inflammation was abrogated in mice lacking IL-1 receptor or ASC, but not NLRP3.
Conclusions:
- Pyrin mutations causing FMF act through a gain-of-function mechanism.
- An ASC-dependent, NLRP3-independent inflammasome pathway is implicated in pyrin-driven autoinflammation.
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