NLRP1 variant M1184V decreases inflammasome activation in the context of DPP9 inhibition and asthma severity.

摘要: Background NLRP1 is an innate immune sensor that can form cytoplasmic inflammasome complexes. Polymorphisms in are linked to asthma; however, there currently no functional or mechanistic explanation for this. Objective We sought clarify the role of asthma pathogenesis. Methods Results from GALA II cohort study were used identify a link between and Mexican Americans. In vitro in vivo models activation applied investigate this at molecular level. document association haplotype with which single nucleotide polymorphism rs11651270 (M1184V) individually most significant. Surprisingly, M1184V increases context N-terminal destabilization, but decreases on dipeptidyl peptidase 9 inhibition. studies demonstrate binding 9, account its inhibitory context. In addition, data mouse model airway inflammation reveal protective reducing eosinophilia setting. Conclusions Linking our in vitro results, we found variant reduces inhibition could thereby increase severity. Our may have implications treatment patients carrying NLRP1.