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 Nlrp1a ^Q593P/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.