title: Alveolar macrophages are sentinels of murine pulmonary homeostasis following inhaled antigen challenge.
abstract: BACKGROUND
  Alveolar macrophages are sentinels of the pulmonary mucosa and central to maintaining immunological homeostasis. However, their role in governing the response to allergen is not fully understood. Inappropriate responses to the inhaled environment manifest as asthma.
  
  
  METHODS
  We utilized a mechanistic IL-13-driven model and a house dust mite allergen mucosal sensitization model of allergic airway disease to investigate the role of alveolar macrophages in regulating pulmonary inflammation.
  
  
  RESULTS
  IL-13-dependent eosinophilic and Th2 inflammation was enhanced in mice depleted of alveolar macrophages using clodronate liposomes. Similarly, depletion of alveolar macrophages during house dust mite sensitization or established disease resulted in augmented Th2 immunity and increased allergen-specific IgG1 and IgE. Clodronate treatment also delayed the resolution of tissue inflammation following cessation of allergen challenge. Strikingly, tissue interstitial macrophages were elevated in alveolar macrophage-deficient mice identifying a new homeostatic relationship between different macrophage subtypes. A novel role for the macrophage-derived immunoregulatory cytokine IL-27 was identified in modulating Th2 inflammation following mucosal allergen exposure.
  
  
  CONCLUSIONS
  In summary, alveolar macrophages are critical regulators of Th2 immunity and their dysregulation promotes an inflammatory environment with exacerbation of allergen-induced airway pathology. Manipulating IL-27 may provide a novel therapeutic strategy for the treatment of asthma.
authors.affiliation: Leukocyte Biology, NHLI, Faculty of Medicine, Imperial College London, London, UK.
authors.forename: S A
authors.initials: SA
authors.lastname: Mathie
authors.forename: K L
authors.initials: KL
authors.lastname: Dixon
authors.forename: S A
authors.initials: SA
authors.lastname: Walker
authors.forename: V
authors.initials: V
authors.lastname: Tyrrell
authors.forename: M
authors.initials: M
authors.lastname: Mondhe
authors.forename: V B
authors.initials: VB
authors.lastname: O'Donnell
authors.forename: L G
authors.initials: LG
authors.lastname: Gregory
authors.forename: C M
authors.initials: CM
authors.lastname: Lloyd
mesh_terms: D000485:Allergens / Q000276:immunology*; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology; D001249:Asthma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006706:Homeostasis; D018793:Interleukin-13 / Q000378:metabolism / Q000494:pharmacology; D064094:Interleukin-27 / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D000485:Allergens; D039741:Antigens, Dermatophagoides; D018793:Interleukin-13; D064094:Interleukin-27
keywords: Alveolar macrophage; homeostasis; house dust mite; interleukin-13; lung