PT - JOURNAL ARTICLE AU - Jay Horvat AU - Richard Kim AU - James Pinkerton AU - Ama-Tawiah Essilfie AU - Avril Robertson AU - Katherine Baines AU - Jemma Mayall AU - Malcolm Starkey AU - Peter Wark AU - Peter Gibson AU - Luke O'Neill AU - Matthew Cooper AU - Philip Hansbro TI - NLRP3 inflammasome-mediated, IL-1β-dependent inflammatory responses drive steroid-resistant asthma AID - 10.1183/13993003.congress-2016.PA564 DP - 2016 Sep 01 TA - European Respiratory Journal PG - PA564 VI - 48 IP - suppl 60 4099 - http://erj.ersjournals.com/content/48/suppl_60/PA564.short 4100 - http://erj.ersjournals.com/content/48/suppl_60/PA564.full SO - Eur Respir J2016 Sep 01; 48 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.