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

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

  • J Allergy Clin Immunol. 2021 Jun;147(6):2134-2145.e20. doi: 10.1016/j.jaci.2020.12.636.
Jonas Moecking 1,  Pawat Laohamonthonkul 2,  Katelyn Chalker 2,  Marquitta J White 3,  Cassandra R Harapas 2,  Chien-Hsiung Yu 2,  Sophia Davidson 2,  Katja Hrovat-Schaale 2,  Donglei Hu 3,  Celeste Eng 3,  Scott Huntsman 3,  Dale J Calleja 2,  Jay C Horvat 4,  Phil M Hansbro 5,  Robert J J O'Donoghue 6,  Jenny P Ting 7,  Esteban G Burchard 8,  Matthias Geyer 9,  Motti Gerlic 10,  Seth L Masters 11
Affiliations

Affiliations

  • 1 Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia; the Institute of Structural Biology, University of Bonn, Venusberg-Campus 1, Bonn, Germany.
  • 2 Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia.
  • 3 Department of Medicine, University of California, San Francisco, Calif.
  • 4 the Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, New Lambton, Australia; University of Newcastle, Callaghan, Australia.
  • 5 the Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, New Lambton, Australia; University of Newcastle, Callaghan, Australia; Centre for Inflammation, Centenary Institute, Sydney, Australia; Faculty of Science, University of Technology Sydney, Ultimo, Australia.
  • 6 Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, Australia.
  • 7 Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC.
  • 8 Department of Medicine, University of California, San Francisco, Calif; Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, San Francisco, Calif.
  • 9 the Institute of Structural Biology, University of Bonn, Venusberg-Campus 1, Bonn, Germany.
  • 10 Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 11 Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia. Electronic address: [email protected].
PMID: 33378691 DOI: 10.1016/j.jaci.2020.12.636
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.

Keywords

DPP9; NLRP1; SNP; asthma; inflammasome.

Figures
Products