Role for NLRP3 inflammasome-mediated, IL-1β-dependent responses in severe, steroid-resistant asthma

Kim, Richard Y., Pinkerton, James W., Essilfie, Ama T., Robertson, Avril A. B., Baines, Katherine J., Brown, Alexandra C., Mayall, Jemma R., Ali, M. Khadem, Starkey, Malcolm R., Hansbro, Nicole G., Hirota, Jeremy A., Wood, Lisa G. , Simpson, Jodie L., Knight, Darryl A., Wark, Peter A., Gibson, Peter G., O'Neill, Luke A. J., Cooper, Matthew A., Horvat, Jay C. and Hansbro, Philip M. (2017) Role for NLRP3 inflammasome-mediated, IL-1β-dependent responses in severe, steroid-resistant asthma. American Journal of Respiratory and Critical Care Medicine, 196 3: 283-297. doi:10.1164/rccm.201609-1830OC

Author Kim, Richard Y.
Pinkerton, James W.
Essilfie, Ama T.
Robertson, Avril A. B.
Baines, Katherine J.
Brown, Alexandra C.
Mayall, Jemma R.
Ali, M. Khadem
Starkey, Malcolm R.
Hansbro, Nicole G.
Hirota, Jeremy A.
Wood, Lisa G.
Simpson, Jodie L.
Knight, Darryl A.
Wark, Peter A.
Gibson, Peter G.
O'Neill, Luke A. J.
Cooper, Matthew A.
Horvat, Jay C.
Hansbro, Philip M.
Title Role for NLRP3 inflammasome-mediated, IL-1β-dependent responses in severe, steroid-resistant asthma
Journal name American Journal of Respiratory and Critical Care Medicine   Check publisher's open access policy
ISSN 1535-4970
Publication date 2017-08-01
Year available 2017
Sub-type Article (original research)
DOI 10.1164/rccm.201609-1830OC
Open Access Status Not yet assessed
Volume 196
Issue 3
Start page 283
End page 297
Total pages 15
Place of publication New York, NY, United States
Publisher American Thoracic Society
Language eng
Subject 2740 Pulmonary and Respiratory Medicine
2706 Critical Care and Intensive Care Medicine
Abstract Rationale: Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identification of therapeutic targets. Excessive nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome and concomitant IL-1β responses occur in chronic obstructive pulmonary disease, respiratory infections, and neutrophilic asthma. However, the direct contributions to pathogenesis, mechanisms involved, and potential for therapeutic targeting remain poorly understood, and are unknown in severe, steroid-resistant asthma. Objectives: To investigate the roles and therapeutic targeting of the NLRP3 inflammasome and IL-1β in severe, steroid-resistant asthma. Methods: We developed mouse models of Chlamydia and Haemophilus respiratory infection-mediated, ovalbumin-induced severe, steroid-resistant allergic airway disease. These models share the hallmark features of human disease, including elevated airway neutrophils, and NLRP3 inflammasome and IL-1β responses. The roles and potential for targeting of NLRP3 inflammasome, caspase-1, and IL-1β responses in experimental severe, steroid-resistant asthma were examined using a highly selective NLRP3 inhibitor, MCC950; the specific caspase-1 inhibitor Ac-YVAD-cho; and neutralizing anti-IL-1β antibody. Roles for IL-1β-induced neutrophilic inflammation were examined using IL-1β and anti-Ly6G. Measurements and Main Results: Chlamydia and Haemophilus infections increase NLRP3, caspase-1, IL-1β responses that drive steroid-resistant neutrophilic inflammation and airway hyperresponsiveness. Neutrophilic airway inflammation, disease severity, and steroid resistance in human asthma correlate with NLRP3 and IL-1β expression. Treatment with anti-IL-1β, Ac- YVAD-cho, and MCC950 suppressed IL-1β responses and the important steroid-resistant features of disease in mice, whereas IL-1β administration recapitulated these features. Neutrophil depletion suppressed IL-1β-induced steroid-resistant airway hyperresponsiveness. Conclusions: NLRP3 inflammasome responses drive experimental severe, steroid-resistant asthma and are potential therapeutic targets in this disease.
Keyword IL-1β
Nucleotide-binding oligomerization domain-like receptor family
Pyrin domain-containing 3
Steroidresistant asthma
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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