title: Role for NLRP3 Inflammasome-mediated, IL-1β-Dependent Responses in Severe, Steroid-Resistant Asthma.
abstract: Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identification of therapeutic targets. Excessive nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome and concomitant IL-1β responses occur in chronic obstructive pulmonary disease, respiratory infections, and neutrophilic asthma. However, the direct contributions to pathogenesis, mechanisms involved, and potential for therapeutic targeting remain poorly understood, and are unknown in severe, steroid-resistant asthma.
  
  
  
  To investigate the roles and therapeutic targeting of the NLRP3 inflammasome and IL-1β in severe, steroid-resistant asthma.
  
  
  
  We developed mouse models of Chlamydia and Haemophilus respiratory infection-mediated, ovalbumin-induced severe, steroid-resistant allergic airway 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 severe, steroid-resistant 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.
  
  
  
  Chlamydia and Haemophilus infections increase NLRP3, caspase-1, IL-1β responses that drive steroid-resistant neutrophilic inflammation and airway hyperresponsiveness. Neutrophilic airway inflammation, disease severity, and steroid resistance in human asthma correlate 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 airway hyperresponsiveness.
  
  
  
  NLRP3 inflammasome responses drive experimental severe, steroid-resistant asthma and are potential therapeutic targets in this disease.
authors.affiliation: 1 Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Richard Y
authors.initials: RY
authors.lastname: Kim
authors.affiliation: 1 Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: James W
authors.initials: JW
authors.lastname: Pinkerton
authors.affiliation: 1 Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Ama T
authors.initials: AT
authors.lastname: Essilfie
authors.affiliation: 2 Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Avril A B
authors.initials: AAB
authors.lastname: Robertson
authors.affiliation: 1 Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Baines
authors.affiliation: 1 Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Brown
authors.affiliation: 1 Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Jemma R
authors.initials: JR
authors.lastname: Mayall
authors.affiliation: 1 Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: M Khadem
authors.initials: MK
authors.lastname: Ali
authors.affiliation: 1 Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Malcolm R
authors.initials: MR
authors.lastname: Starkey
authors.affiliation: 1 Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Nicole G
authors.initials: NG
authors.lastname: Hansbro
authors.affiliation: 3 James Hogg Research Centre, University of British Columbia, Vancouver, British Columbia, Canada; and.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Hirota
authors.affiliation: 1 Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Wood
authors.affiliation: 1 Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Jodie L
authors.initials: JL
authors.lastname: Simpson
authors.affiliation: 1 Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Darryl A
authors.initials: DA
authors.lastname: Knight
authors.affiliation: 1 Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Wark
authors.affiliation: 1 Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Gibson
authors.affiliation: 4 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Luke A J
authors.initials: LAJ
authors.lastname: O'Neill
authors.affiliation: 2 Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
authors.affiliation: 1 Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Jay C
authors.initials: JC
authors.lastname: Horvat
authors.affiliation: 1 Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hansbro
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D004351:Drug Resistance; D053583:Interleukin-1beta / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse
keywords: IL-1β; MCC950; nucleotide-binding oligomerization domain–like receptor family; pyrin domain–containing 3; steroid-resistant asthma