Inflammasomes in severe asthma

Kim RY1, Pinkerton JW1, Essilfie AT1, Robertson AAB2, Baines KJ1, Brown AC1, Mayall JR1, Ali K1, Starkey MR1, Hansbro NG1, Hirota JA3, Wood LG1, Simpson JL1, Knight DA1, Wark PA1, Gibson PG1, O’Neill LAJ4, Cooper MA2, Horvat JC1 and Hansbro PM1

  1. University of Newcastle, Newcastle, New South Wales, Australia.
  2. University of Queensland, Brisbane, Queensland, Australia.
  3. University of British Columbia, Vancouver, British Columbia, Canada.
  4. Trinity College Dublin, Dublin, Ireland.

Rationale: Severe, steroid-resistant (SSR) asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identification of therapeutic targets. Excessive NLRP3 inflammasome and concomitant IL-1β responses occur in COPD, respiratory infections and neutrophilic asthma. However, the direct contributions to pathogenesis, mechanisms involved and potential for therapeutic targeting are unknown in SSR asthma. Methods: We developed mouse models of Chlamydia, and Haemophilus, respiratory infection-mediated, ovalbumin-induced SSR allergic airways 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 SSR 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. Results: Chlamydia and Haemophilus infections increase NLRP3, caspase-1, IL-1β responses that drive steroid-resistant neutrophilic inflammation and airways hyper-responsiveness (AHR). Neutrophilic inflammation, disease severity and steroid-resistance in human asthma correlates with NLRP3 and IL-1β expression. Treatment with anti-IL-1β, Ac-YVAD-cho, and MCC950 suppressed IL-1β responses and the important steroid-resistant features of disease in mice, whereas IL-1β administration recapitulated these features. Neutrophil depletion suppressed IL-1β-induced steroid-resistant AHR. Conclusions: NLRP3 inflammasome responses drive experimental SSR asthma and are potential therapeutic targets in this disease.