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OR11-006 - A mutation in NLRP1A causes autoinflammation


The NLRs (Nucleotide-binding domain and Leucine-rich repeat containing Receptors) are a family of intracellular innate immune receptors involved in host defense. Upon activation, NLRs form large protein complexes called “inflammasomes” that bind and activate Caspase-1, resulting in proteolytic activation of the pro-inflammatory cytokines pro-IL-1β and pro-IL-18 and also induce a Caspase-1-dependent form of cell death known as pyroptosis.


Activating mutations in NLRP3 trigger the inflammasome and cause a spectrum of auto-inflammatory disease. Therefore our objective was to establish if activating mutations in NLRP1 also cause autoinflammatory disease.


We performed an N-ethyl-N-nitrosourea (ENU) mutagenesis screen for dominant mutations that cause neutrophilia in G1 mice and isolated a pedigree with a mutation in NLRP1a.


Mice with the mutation Nlrp1a+/Q593P were fertile and remained healthy to at least 8 months of age, despite histological evidence of a multi-organ neutrophilic inflammatory disease characterised by meningitis, hepatitis, pneumonitis, pancreatitis, pulmonary peri-arteritis, myocarditis and inflammatory bowel disease. In Nlrp1aQ593P/Q593P homozygotes, a similar but lethal condition developed by 3-5 months of age. Neutrophil counts in these animals were 15-fold higher than wild-type, and they exhibited lymphopenia and splenomegaly. By breeding with genetically deficient mice we showed that the lethal systemic inflammatory disease was ameliorated by removing Caspase-1 and IL-1R but was independent of ASC. On the other hand, deletion of IL-18 increased the number of neutrophils in the blood, and greatly accelerated the onset of disease.


In summary we show for the first time in vivo the effect of an activating mutation in NLRP1, which causes autoinflammatory disease. We demonstrate that this disease is caused by IL-1β and Caspase-1, but not ASC. Surprisingly, IL-18 is beneficial for this condition, suggesting that caution should be employed when blocking IL-18 in human autoinflammatory diseases. Our results strongly suggest that mutations in human NLRP1 would cause autoinflammatory disease.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Masters, S., Gerlic, M., Kile, B. et al. OR11-006 - A mutation in NLRP1A causes autoinflammation. Pediatr Rheumatol 11 (Suppl 1), A195 (2013).

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