title: Macrophage activation state determines the response to rhinovirus infection in a mouse model of allergic asthma.
abstract: BACKGROUND
  The mechanisms by which viruses cause asthma exacerbations are not precisely known. Previously, we showed that, in ovalbumin (OVA)-sensitized and -challenged mice with allergic airway inflammation, rhinovirus (RV) infection increases type 2 cytokine production from alternatively-activated (M2) airway macrophages, enhancing eosinophilic inflammation and airways hyperresponsiveness. In this paper, we tested the hypothesis that IL-4 signaling determines the state of macrophage activation and pattern of RV-induced exacerbation in mice with allergic airways disease.
  
  
  METHODS
  Eight week-old wild type or IL-4 receptor knockout (IL-4R KO) mice were sensitized and challenged with OVA and inoculated with RV1B or sham HeLa cell lysate.
  
  
  RESULTS
  In contrast to OVA-treated wild-type mice with both neutrophilic and eosinophilic airway inflammation, OVA-treated IL-4R KO mice showed increased neutrophilic inflammation with few eosinophils in the airways. Like wild-type mice, IL-4R KO mice showed OVA-induced airway hyperreactivity which was further exacerbated by RV. There was a shift in lung cytokines from a type 2-predominant response to a type 1 response, including production of IL-12p40 and TNF-α. IL-17A was also increased. RV infection of OVA-treated IL-4R KO mice further increased neutrophilic inflammation. Bronchoalveolar macrophages showed an M1 polarization pattern and ex vivo RV infection increased macrophage production of TNF-α, IFN-γ and IL-12p40. Finally, lung cells from OVA-treated IL-4R KO mice showed reduced CD206+ CD301+ M2 macrophages, decreased IL-13 and increased TNF-α and IL-17A production by F4/80+, CD11b+ macrophages.
  
  
  CONCLUSIONS
  OVA-treated IL-4R KO mice show neutrophilic airway inflammation constituting a model of allergic, type 1 cytokine-driven neutrophilic asthma. In the absence of IL-4/IL-13 signaling, RV infection of OVA-treated mice increased type 1 cytokine and IL-17A production from conventionally-activated macrophages, augmenting neutrophilic rather than eosinophilic inflammation. In mice with allergic airways inflammation, IL-4R signaling determines macrophage activation state and the response to subsequent RV infection.
authors.forename: Jun Young
authors.initials: JY
authors.lastname: Hong
authors.forename: Yutein
authors.initials: Y
authors.lastname: Chung
authors.forename: Jessica
authors.initials: J
authors.lastname: Steenrod
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Lei
authors.forename: Adam T
authors.initials: AT
authors.lastname: Comstock
authors.forename: Adam M
authors.initials: AM
authors.lastname: Goldsmith
authors.forename: J Kelley
authors.initials: JK
authors.lastname: Bentley
authors.forename: Uma S
authors.initials: US
authors.lastname: Sajjan
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, 48109 Ann Arbor, MI, USA. mhershen@umich.edu.
authors.forename: Marc B
authors.initials: MB
authors.lastname: Hershenson
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism*; D008262:Macrophage Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D065631:Rhinitis, Allergic; D012221:Rhinitis, Allergic, Perennial / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012229:Rhinovirus
chemical_list: D015847:Interleukin-4