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

Jonas Moecking, Pawat Laohamonthonkul, Katelyn Chalker, Marquitta J. White, Cassandra R. Harapas, Chien Hsiung Yu, Sophia Davidson, Katja Hrovat-Schaale, Donglei Hu, Celeste Eng, Scott Huntsman, Dale J. Calleja, Jay C. Horvat, Phil M. Hansbro, Robert J.J. O'Donoghue, Jenny P. Ting, Esteban G. Burchard, Matthias Geyer, Motti Gerlic, Seth L. Masters*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish
Pages (from-to)2134-2145.e20
JournalJournal of Allergy and Clinical Immunology
Volume147
Issue number6
DOIs
StatePublished - Jun 2021

Funding

FundersFunder number
Sandler Foundation
Victorian Endowment for Science Knowledge and Innovation
RWJF Amos Medical Faculty Development Program
Ormond College's Thwaites Gutch
National Institutes of Health
Ormond College’s Thwaites Gutch
Severns Family Foundation
HHMI-Wellcome
WEHI
American Asthma Foundation/Sandler Foundation.We
Sylvia and Charles Viertel Foundation
American Asthma Foundation
Israel Science Foundation1416/15, 818/18
National Institute of Allergy and Infectious DiseasesR01AI029564, U19AI077437
National Heart, Lung, and Blood InstituteK01HL140218, R01HL117004, R01HL141992, R01HL135156, R01HL120393, R01HL128439, R01HL117626, R01HL141845, X01HL134589
University of MichiganHHSN268201800001I, HHSN268201800002I, 3R01HL-117626-02S1, 3R01HL-120393-02S1
National Human Genome Research InstituteU01HG009080
Recanati Foundation390873048, EXC2151, EXC2151 – 390873048
National Health and Medical Research Council1120252, 1079187, 1057815, 1143412, GNT1143412, 1099262, 1175134
National Institute of Environmental Health SciencesR01ES015794, R21ES024844
National Institute of General Medical SciencesRL5GM118984
National Institute on Minority Health and Health DisparitiesP60MD006902, R56MD013312, R01MD010443
Deutsche ForschungsgemeinschaftGRK 2168
Alpha-1 Foundation615533

    Keywords

    • DPP9
    • NLRP1
    • SNP
    • asthma
    • inflammasome

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