RT Journal Article
SR Electronic
T1 NLRP3 inflammasome-mediated, IL-1β-dependent inflammatory responses drive steroid-resistant asthma
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP PA564
DO 10.1183/13993003.congress-2016.PA564
VO 48
IS suppl 60
A1 Horvat, Jay
A1 Kim, Richard
A1 Pinkerton, James
A1 Essilfie, Ama-Tawiah
A1 Robertson, Avril
A1 Baines, Katherine
A1 Mayall, Jemma
A1 Starkey, Malcolm
A1 Wark, Peter
A1 Gibson, Peter
A1 O'Neill, Luke
A1 Cooper, Matthew
A1 Hansbro, Philip
YR 2016
UL http://erj.ersjournals.com/content/48/suppl_60/PA564.abstract
AB Introduction: Excessive NLRP3 inflammasome and concomitant IL-1β responses are implicated in many inflammatory diseases. However, the direct contributions to pathogenesis, mechanisms involved and potential for therapeutic targeting remain poorly understood. In the lung, NLRP3 inflammasome and IL-1β are associated with emphysema, infections and steroid-resistant (SR) asthma, which is the major unmet clinical need in asthma management.Aim: To investigate the role of the NLRP3 inflammasome and IL-1β in SR asthma.Methods: We developed mouse models of Chlamydia, and Haemophilus, respiratory infection-mediated, ovalbumin-induced SR allergic airways disease (SRAAD). These models share the hallmark features of human disease, including elevated neutrophils in the airways, NLRP3 inflammasome and IL-1β responses. The roles and potential for targeting of NLRP3 inflammasome, caspase-(CASP)1, and IL-1β responses in the lung in SRAAD were examined using a highly-selective NLRP3 inhibitor, MCC950, the specific CASP1 inhibitor, Ac-YVAD-cho, and neutralising anti-IL-1β antibody, α-IL-1β, respectively.Results: We show that Chlamydia and Haemophilus infections increase NLRP3, CASP1, IL-1β and TH1/17 responses that drive steroid-resistant neutrophilic inflammation and airways hyper-responsiveness in SRAAD. Neutrophilic airway inflammation and severity of human SR asthma correlated with IL-1β and NLRP3 expression. Treatment with α-IL-1β , Ac-YVAD-cho, and MCC950 suppressed IL-1β responses and the important steroid-resistant features of disease.Conclusions: NLRP3 inflammasome responses may drive SR asthma and be therapeutically targeted in this and other NLRP3-mediated diseases.