Source: International Congress 2016 – Asthma: mechanisms and biomarkers that promote clinical understanding
Disease area: Airway diseases

Abstract

Introduction: Excessive NLRP3 inflammasome and concomitant IL-1b 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-1b 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-1b 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-1b responses. The roles and potential for targeting of NLRP3 inflammasome, caspase-(CASP)1, and IL-1b 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-1b antibody, a-IL-1b, respectively. Results: We show that Chlamydia and Haemophilus infections increase NLRP3, CASP1, IL-1b and T_H1/17 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-1b and NLRP3 expression. Treatment with a-IL-1b , Ac-YVAD-cho, and MCC950 suppressed IL-1b 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.


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Jay Horvat (Newcastle, Australia), Jay Horvat, Richard Kim, James Pinkerton, Ama-Tawiah Essilfie, Avril Robertson, Katherine Baines, Jemma Mayall, Malcolm Starkey, Peter Wark, Peter Gibson, Luke O’Neill, Matthew Cooper, Philip Hansbro. NLRP3 inflammasome-mediated, IL-1β-dependent inflammatory responses drive steroid-resistant asthma. Eur Respir J 2016; 48: Suppl. 60, 564

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