title: Rhinovirus infection of allergen-sensitized and -challenged mice induces eotaxin release from functionally polarized macrophages.
abstract: Human rhinovirus is responsible for the majority of virus-induced asthma exacerbations. To determine the immunologic mechanisms underlying rhinovirus (RV)-induced asthma exacerbations, we combined mouse models of allergic airways disease and human rhinovirus infection. We inoculated OVA-sensitized and challenged BALB/c mice with rhinovirus serotype 1B, a minor group strain capable of infecting mouse cells. Compared with sham-infected, OVA-treated mice, virus-infected mice showed increased lung infiltration with neutrophils, eosinophils and macrophages, airway cholinergic hyperresponsiveness, and increased lung expression of cytokines including eotaxin-1/CCL11, IL-4, IL-13, and IFN-gamma. Administration of anti-eotaxin-1 attenuated rhinovirus-induced airway eosinophilia and responsiveness. Immunohistochemical analysis showed eotaxin-1 in the lung macrophages of virus-infected, OVA-treated mice, and confocal fluorescence microscopy revealed colocalization of rhinovirus, eotaxin-1, and IL-4 in CD68-positive cells. RV inoculation of lung macrophages from OVA-treated, but not PBS-treated, mice induced expression of eotaxin-1, IL-4, and IL-13 ex vivo. Macrophages from OVA-treated mice showed increased expression of arginase-1, Ym-1, Mgl-2, and IL-10, indicating a shift in macrophage activation status. Depletion of macrophages from OVA-sensitized and -challenged mice reduced eosinophilic inflammation and airways responsiveness following RV infection. We conclude that augmented airway eosinophilic inflammation and hyperresponsiveness in RV-infected mice with allergic airways disease is directed in part by eotaxin-1. Airway macrophages from mice with allergic airways disease demonstrate a change in activation state characterized in part by altered eotaxin and IL-4 production in response to RV infection. These data provide a new paradigm to explain RV-induced asthma exacerbations.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Deepti R
authors.initials: DR
authors.lastname: Nagarkar
authors.forename: Emily R
authors.initials: ER
authors.lastname: Bowman
authors.forename: Dina
authors.initials: D
authors.lastname: Schneider
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wang
authors.forename: Jee
authors.initials: J
authors.lastname: Shim
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.forename: Marisa J
authors.initials: MJ
authors.lastname: Linn
authors.forename: Christina L
authors.initials: CL
authors.lastname: McHenry
authors.forename: Babina
authors.initials: B
authors.lastname: Gosangi
authors.forename: J Kelley
authors.initials: JK
authors.lastname: Bentley
authors.forename: Wan C
authors.initials: WC
authors.lastname: Tsai
authors.forename: Umadevi S
authors.initials: US
authors.lastname: Sajjan
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Lukacs
authors.forename: Marc B
authors.initials: MB
authors.lastname: Hershenson
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000378:metabolism; D054413:Chemokine CCL11 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D010047:Ovalbumin / Q000276:immunology*; D010850:Picornaviridae Infections / Q000276:immunology* / Q000821:virology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012229:Rhinovirus / Q000276:immunology; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D054413:Chemokine CCL11; D016207:Cytokines; D018836:Inflammation Mediators; D010047:Ovalbumin; C081026:CD68 protein, mouse; D000097382:CD68 Molecule