title: GM-CSF treatment prevents respiratory syncytial virus-induced pulmonary exacerbation responses in postallergic mice by stimulating alveolar macrophage maturation.
abstract: BACKGROUND
  Human respiratory syncytial virus (RSV) is a frequent cause of asthma exacerbations, yet the susceptibility of asthmatic patients to RSV is poorly understood.
  
  
  OBJECTIVE
  We sought to address the contribution of resident alveolar macrophages (rAMs) to susceptibility to RSV infection in mice that recovered from allergic airway eosinophilia.
  
  
  METHODS
  Mice were infected with RSV virus after clearance of allergic airway inflammation (AAI). The contribution of post-AAI rAMs was studied in vivo by means of clodronate liposome-mediated depletion, adoptive transfer, and treatment with recombinant cytokines before RSV infection.
  
  
  RESULTS
  After clearing the allergic bronchial inflammation, post-AAI mice had bronchial hyperreactivity and increased inflammatory cell influx when infected with RSV compared with nonallergic mice, whereas viral clearance was comparable in both mouse groups. Post-AAI rAMs were necessary and sufficient for mediating these proinflammatory effects. In post-AAI mice the residing CD11c(hi) autofluorescent rAM population did not upregulate the terminal differentiation marker sialic acid-binding immunoglobulin-like lectin F and overproduced TNF and IL-6 through increased nuclear factor κB nuclear translocation. In line with these results, post-AAI lungs had reduced levels of the rAM maturation cytokine GM-CSF. Intratracheal administration of GM-CSF induced final rAM maturation in post-AAI mice and prevented the increased susceptibility to RSV-induced hyperreactivity and inflammation.
  
  
  CONCLUSIONS
  Defective production of GM-CSF leads to insufficient post-AAI rAM maturation in mice that recovered from an AAI, causing increased susceptibility to RSV-induced immunopathology. Promoting the differentiation of post-AAI rAMs might be a therapeutic option for preventing RSV-induced exacerbations in human asthmatic patients.
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Naessens
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Inflammation Research Center, VIB, Ghent, Belgium.
authors.forename: Bert
authors.initials: B
authors.lastname: Schepens
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Muriel
authors.initials: M
authors.lastname: Smet
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Pollard
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: Van Hoecke
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Ans
authors.initials: A
authors.lastname: De Beuckelaer
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium; Department of Pulmonary Medicine, Ghent University, Ghent, Belgium.
authors.forename: Monique
authors.initials: M
authors.lastname: Willart
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium; Department of Pulmonary Medicine, Ghent University, Ghent, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Lambrecht
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Stefaan
authors.initials: S
authors.lastname: De Koker
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Inflammation Research Center, VIB, Ghent, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Saelens
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. Electronic address: Johan.Grooten@ugent.be.
authors.forename: Johan
authors.initials: J
authors.lastname: Grooten
mesh_terms: D019264:Adoptive Transfer; D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000150:complications* / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D018357:Respiratory Syncytial Virus Infections / Q000150:complications* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018113:Respiratory Syncytial Virus, Human
chemical_list: D000485:Allergens; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Allergic asthma; GM-CSF; alveolar macrophage; respiratory syncytial virus–induced exacerbation