title: Alternaria-derived serine protease activity drives IL-33-mediated asthma exacerbations.
abstract: BACKGROUND
  The fungal allergen Alternaria alternata is implicated in severe asthma and rapid onset life-threatening exacerbations of disease. However, the mechanisms that underlie this severe pathogenicity remain unclear.
  
  
  OBJECTIVE
  We sought to investigate the mechanism whereby Alternaria was capable of initiating severe, rapid onset allergic inflammation.
  
  
  METHODS
  IL-33 levels were quantified in wild-type and ST2(-/-) mice that lacked the IL-33 receptor given inhaled house dust mite, cat dander, or Alternaria, and the effect of inhibiting allergen-specific protease activities on IL-33 levels was assessed. An exacerbation model of allergic airway disease was established whereby mice were sensitized with house dust mite before subsequently being challenged with Alternaria (with or without serine protease activity), and inflammation, remodeling, and lung function assessed 24 hours later.
  
  
  RESULTS
  Alternaria, but not other common aeroallergens, possessed intrinsic serine protease activity that elicited the rapid release of IL-33 into the airways of mice through a mechanism that was dependent upon the activation of protease activated receptor-2 and adenosine triphosphate signaling. The unique capacity of Alternaria to drive this early IL-33 release resulted in a greater pulmonary inflammation by 24 hours after challenge relative to the common aeroallergen house dust mite. Furthermore, this Alternaria serine protease-IL-33 axis triggered a rapid, augmented inflammation, mucus release, and loss of lung function in our exacerbation model.
  
  
  CONCLUSIONS
  Alternaria-specific serine protease activity causes rapid IL-33 release, which underlies the development of a robust TH2 inflammation and exacerbation of allergic airway disease.
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Snelgrove
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Gregory
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Teresa
authors.initials: T
authors.lastname: Peiró
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Samia
authors.initials: S
authors.lastname: Akthar
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Gaynor A
authors.initials: GA
authors.lastname: Campbell
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Simone A
authors.initials: SA
authors.lastname: Walker
authors.affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom. Electronic address: c.lloyd@imperial.ac.uk.
authors.forename: Clare M
authors.initials: CM
authors.lastname: Lloyd
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000528:Alternaria / Q000276:immunology*; D060487:Alternariosis / Q000276:immunology / Q000382:microbiology*; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005656:Fungal Proteins / Q000276:immunology*; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology / Q000382:microbiology*; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D039981:Pyroglyphidae; D044464:Receptor, PAR-2 / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics; D057057:Serine Proteases / Q000276:immunology*; D015398:Signal Transduction
chemical_list: D039741:Antigens, Dermatophagoides; D005656:Fungal Proteins; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D044464:Receptor, PAR-2; D018123:Receptors, Interleukin; D000255:Adenosine Triphosphate; D057057:Serine Proteases
keywords: Alternaria alternata; IL-33; allergic airway disease; asthma exacerbation; protease