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

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
European Respiratory Journal 2016 48: PA564; DOI: 10.1183/13993003.congress-2016.PA564
Jay Horvat
1Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, New South WalesAustralia
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Richard Kim
1Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, New South WalesAustralia
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James Pinkerton
1Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, New South WalesAustralia
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Ama-Tawiah Essilfie
1Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, New South WalesAustralia
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Avril Robertson
2Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QueenslandAustralia
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Katherine Baines
1Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, New South WalesAustralia
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Jemma Mayall
1Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, New South WalesAustralia
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Malcolm Starkey
1Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, New South WalesAustralia
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Peter Wark
1Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, New South WalesAustralia
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Peter Gibson
1Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, New South WalesAustralia
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Luke O'Neill
3School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
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Matthew Cooper
2Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QueenslandAustralia
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Philip Hansbro
1Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, New South WalesAustralia
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Abstract

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.

  • Asthma - management
  • Immunology
  • Infections
  • Copyright ©the authors 2016
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NLRP3 inflammasome-mediated, IL-1β-dependent inflammatory responses drive steroid-resistant asthma
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
European Respiratory Journal Sep 2016, 48 (suppl 60) PA564; DOI: 10.1183/13993003.congress-2016.PA564

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NLRP3 inflammasome-mediated, IL-1β-dependent inflammatory responses drive steroid-resistant asthma
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
European Respiratory Journal Sep 2016, 48 (suppl 60) PA564; DOI: 10.1183/13993003.congress-2016.PA564
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