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

Moecking, J; Laohamonthonkul, P; Chalker, K; White, MJ; Harapas, CR; Yu, CH; Davidson, S; Schaale, KH; Hu, D; Eng, C; Huntsman, S; Calleja, DJ; Horvat, JC; Hansbro, PM; O&#39;Donoghue, RJJ; Ting, JP; Burchard, EG; Geyer, M; Gerlic, M; Masters, SL

Author(s): Moecking, J; Laohamonthonkul, P; Chalker, K; White, MJ; Harapas, CR; Yu, CH; Davidson, S; Schaale, KH; Hu, D; Eng, C; Huntsman, S; Calleja, DJ; Horvat, JC; Hansbro, PM; O'Donoghue, RJJ; Ting, JP; Burchard, EG; Geyer, M; Gerlic, M; Masters, SL;
Details: Publication Year 2020-12-27,Volume 147,Issue #6,Page 2134-2145.e20
Journal Title: J Allergy Clin Immunol
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 aimed 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 SNP rs11651270 (M1184V) individually is the most significant. Surprisingly, M1184V increases NLRP1 activation in the context of N-terminal destabilization, but decreases NLRP1 activation upon DPP9 inhibition. In vitro studies demonstrate that M1184V increases binding to DPP9, which can account for its inhibitory role in this context. Additionally, in vivo data from a mouse model of airway inflammation reveal a protective role for NLRP1 inflammasome activation reducing eosinophilia in this setting. CONCLUSION: Linking our in vitro and in vivo results, the NLRP1 variant M1184V reduces inflammasome activation in the context of DPP9 inhibition and could thereby increase asthma severity. Our studies may have implications for the treatment of asthma in patients carrying this variant of NLRP1.
Publisher: Elsevier
Keywords: Dpp9; Nlrp1; Snp; asthma; inflammasome
Research Division(s): Inflammation
PubMed ID: 33378691
Publisher's Version: https://doi.org/10.1016/j.jaci.2020.12.636
Open Access at Publisher's Site: https://doi.org/10.1016/j.jaci.2020.12.636
Terms of Use/Rights Notice: Refer to copyright notice on published article.
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Creation Date: 2021-02-01 12:08:35

Last Modified: 2021-08-03 02:02:40