Role for NLRP3 Inflammasome-mediated, IL-1β-Dependent Responses in Severe, Steroid-Resistant Asthma.
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: 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: CONCLUSIONS: NLRP3 inflammasome responses drive experimental severe, steroid-resistant asthma and are potential therapeutic targets in this disease.
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Authors | Richard Y Kim, James W Pinkerton, Ama T Essilfie, Avril A B Robertson, Katherine J Baines, Alexandra C Brown, Jemma R Mayall, M Khadem Ali, Malcolm R Starkey, Nicole G Hansbro, Jeremy A Hirota, Lisa G Wood, Jodie L Simpson, Darryl A Knight, Peter A Wark, Peter G Gibson, Luke A J O'Neill, Matthew A Cooper, Jay C Horvat, Philip M Hansbro |
Journal | American journal of respiratory and critical care medicine
(Am J Respir Crit Care Med)
Vol. 196
Issue 3
Pg. 283-297
(08 01 2017)
ISSN: 1535-4970 [Electronic] United States |
PMID | 28252317
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Interleukin-1beta
- NLR Family, Pyrin Domain-Containing 3 Protein
- Nlrp3 protein, mouse
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Topics |
- Animals
- Asthma
(genetics, immunology, metabolism)
- Disease Models, Animal
- Drug Resistance
- Interleukin-1beta
(genetics, immunology, metabolism)
- Mice
- Mice, Inbred BALB C
- NLR Family, Pyrin Domain-Containing 3 Protein
(genetics, immunology, metabolism)
- Severity of Illness Index
- Treatment Outcome
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