1. NLRP1 variant M1184V decreases inflammasome activation in the context of DPP9 inhibition and asthma severity.
- Author
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Moecking J, Laohamonthonkul P, Chalker K, White MJ, Harapas CR, Yu CH, Davidson S, Hrovat-Schaale K, Hu D, Eng C, Huntsman S, Calleja DJ, Horvat JC, Hansbro PM, O'Donoghue RJJ, Ting JP, Burchard EG, Geyer M, Gerlic M, and Masters SL
- Subjects
- Amino Acid Sequence, Amino Acid Substitution, Animals, Asthma diagnosis, Cell Line, Disease Models, Animal, Disease Susceptibility, Eosinophils immunology, Eosinophils metabolism, Eosinophils pathology, Genetic Predisposition to Disease, Humans, Mice, Mice, Knockout, NLR Proteins chemistry, NLR Proteins metabolism, Polymorphism, Single Nucleotide, Structure-Activity Relationship, Trauma Severity Indices, Alleles, Asthma etiology, Asthma metabolism, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases antagonists & inhibitors, Inflammasomes metabolism, Mutation, NLR Proteins genetics
- Abstract
Background: NLRP1 is an innate immune sensor that can form cytoplasmic inflammasome complexes. Polymorphisms in NLRP1 are linked to asthma; however, there is currently no functional or mechanistic explanation for this., Objective: We sought to clarify the role of NLRP1 in asthma pathogenesis., Methods: Results from the GALA II cohort study were used to identify a link between NLRP1 and asthma in Mexican Americans. In vitro and in vivo models for NLRP1 activation were applied to investigate the role of this inflammasome in asthma at the molecular level., Results: We document the association of an NLRP1 haplotype with asthma for which the single nucleotide polymorphism rs11651270 (M1184V) individually is the most significant. Surprisingly, M1184V increases NLRP1 activation in the context of N-terminal destabilization, but decreases NLRP1 activation on dipeptidyl peptidase 9 inhibition. In vitro studies demonstrate that M1184V increases binding to dipeptidyl peptidase 9, which can account for its inhibitory role in this context. In addition, in vivo data from a mouse model of airway inflammation reveal a protective role for NLRP1 inflammasome activation reducing eosinophilia in this setting., Conclusions: Linking our in vitro and in vivo results, we found that the NLRP1 variant M1184V reduces inflammasome activation in the context of dipeptidyl peptidase 9 inhibition and could thereby increase asthma severity. Our studies may have implications for the treatment of asthma in patients carrying this variant of NLRP1., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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