NLRP3 inflammasome-mediated, IL-1β-dependent inflammatory responses drive steroid-resistant asthma

<b>Introduction:</b> 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. <b>Aim:</b> To investigate the role of the NLRP3 inflammasome and IL-1β in SR asthma. <b>Methods:</b> We developed mouse models of <i>Chlamydia</i>, and <i>Haemophilus</i>, 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. <b>Results:</b> We show that <i>Chlamydia</i> and <i>Haemophilus</i> infections increase NLRP3, CASP1, IL-1β 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-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. <b>Conclusions:</b> NLRP3 inflammasome responses may drive SR asthma and be therapeutically targeted in this and other NLRP3-mediated diseases.