Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity
Open accessAbstract
NLRP3 nucleates the inflammasome, a protein complex responsible for cleavage of prointerleukin-1beta (IL-1beta) to its active form. Mutations in the NLRP3 gene cause the autoinflammatory disease spectrum cryopyrin-associated periodic syndromes (CAPS). The central role of IL-1beta in CAPS is supported by the response to IL-1-targeted therapy. We developed two Nlrp3 mutant knockin mouse strains to model CAPS to examine the role of other inflammatory mediators and adaptive immune responses in an innate immune-driven disease. These mice had systemic inflammation and poor growth, similar to some human CAPS patients, and demonstrated early mortality, primarily mediated by myeloid cells. Mating these mutant mice to various gene mutant backgrounds showed that the mouse disease phenotype required an intact inflammasome, was only partially dependent on IL-1beta, and was independent of T cells. These data suggest that CAPS are true inflammasome-mediated diseases and provide insight for more common inflammatory disorders.
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BMDMs carrying disease-relevant Nlrp3 mutations (L351P and A350V, corresponding to human L353P and A352V) confer constitutive NLRP3 activity.
“Using BMDMs carrying disease-relevant Nlrp3 mutations (L351P and A350V, corresponding to human L353P and A352V) that confer constitutive NLRP3 activity,60”
From Taurine lowers inflammaging by regulating the NLRP3 inflammasome in macrophages (2026) · cites this paper as [60]
The Results sections on mouse-strain development and inflammasome function identify A350V and L351P as the mouse counterparts of the disease-associated human mutations and show enhanced IL-1β release from mutant cells without added ATP. But the experiments described use bone-marrow-derived dendritic cells (BMDCs) and peritoneal macrophages, not BMDMs. The paper calls constitutive inflammasome activity a hypothesis; it reports unstimulated IL-1β release only for L351P BMDCs, not for both mutations. (LLM, conf=0.88)
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- Authors
- Brydges, S. D., Mueller, J. L., McGeough, M. D., Pena, C. A., Misaghi, A., Gandhi, C., Putnam, C. D., Boyle, D. L., Firestein, G. S., Horner, A. A., Soroosh, P., Watford, W. T., O'Shea, J. J., Kastner, D. L., & Hoffman, H. M.
- Affiliations
- National Institutes of Health (US)
- University of California San Diego (US)
- La Jolla Institute for Immunology (US)
- Corresponding author
- Hoffman, Hal M.
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2009-06
- Volume
- 30
- Issue
- 6
- Pages
- 875-887
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC2759865
- OpenAlex
- W2028857382
- Cited by
- 339
- References
- 5
- Citations by year
- 2026: 11 · 2025: 9 · 2024: 23 · 2023: 23 · 2022: 22 · 2021: 22 · 2020: 16 · 2019: 18 · 2018: 24 · 2017: 31 · 2016: 12 · 2015: 20 · 2014: 17 · 2013: 25 · 2012: 18
- FWCI
- 8.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01 AI 52430, R21AI061108, R01AI052430)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Keywords
- NLRP3 inflammasome, cryopyrin-associated periodic syndromes, IL-1β, innate immunity, adaptive immunity, T cells, myeloid cells, autoinflammatory disease, systemic inflammation, disease modeling
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, B-Lymphocytes, Carrier Proteins, Disease Models, Animal, Immunity, Active, Immunity, Innate, Inflammation, Mice, Mutant Strains, Mutation, T-Lymphocytes, Cytokines, Interleukin-18, Mice, Interleukin-1beta, Gene Knock-In Techniques
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