title: Macrophage/epithelial cell CCL2 contributes to rhinovirus-induced hyperresponsiveness and inflammation in a mouse model of allergic airways disease.
abstract: Human rhinovirus (HRV) infections lead to exacerbations of lower airways disease in asthmatic patients but not in healthy individuals. However, underlying mechanisms remain to be completely elucidated. We hypothesized that the Th2-driven allergic environment enhances HRV-induced CC chemokine production, leading to asthma exacerbations. Ovalbumin (OVA)-sensitized and -challenged mice inoculated with HRV showed significant increases in the expression of lung CC chemokine ligand (CCL)-2/monocyte chemotactic protein (MCP)-1, CCL4/macrophage inflammatory protein (MIP)-1β, CCL7/MCP-3, CCL19/MIP-3β, and CCL20/MIP3α compared with mice treated with OVA alone. Inhibition of CCL2 with neutralizing antibody significantly attenuated HRV-induced airways inflammation and hyperresponsiveness in OVA-treated mice. Immunohistochemical stains showed colocalization of CCL2 with HRV in epithelial cells and CD68-positive macrophages, and flow cytometry showed increased CCL2(+), CD11b(+) cells in the lungs of OVA-treated, HRV-infected mice. Compared with lung macrophages from naïve mice, macrophages from OVA-exposed mice expressed significantly more CCL2 in response to HRV infection ex vivo. Pretreatment of mouse lung macrophages and BEAS-2B human bronchial epithelial cells with interleukin (IL)-4 and IL-13 increased HRV-induced CCL2 expression, and mouse lung macrophages from IL-4 receptor knockout mice showed reduced CCL2 expression in response to HRV, suggesting that exposure to these Th2 cytokines plays a role in the altered HRV response. Finally, bronchoalveolar macrophages from children with asthma elaborated more CCL2 upon ex vivo exposure to HRV than cells from nonasthmatic patients. We conclude that CCL2 production by epithelial cells and macrophages contributes to HRV-induced airway hyperresponsiveness and inflammation in a mouse model of allergic airways disease and may play a role in HRV-induced asthma exacerbations.
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Dina
authors.initials: D
authors.lastname: Schneider
authors.forename: Jun Young
authors.initials: JY
authors.lastname: Hong
authors.forename: Emily R
authors.initials: ER
authors.lastname: Bowman
authors.forename: Yutein
authors.initials: Y
authors.lastname: Chung
authors.forename: Deepti R
authors.initials: DR
authors.lastname: Nagarkar
authors.forename: Christina L
authors.initials: CL
authors.lastname: McHenry
authors.forename: Adam M
authors.initials: AM
authors.lastname: Goldsmith
authors.forename: J Kelley
authors.initials: JK
authors.lastname: Bentley
authors.forename: Toby C
authors.initials: TC
authors.lastname: Lewis
authors.forename: Marc B
authors.initials: MB
authors.lastname: Hershenson
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000276:immunology; D054415:Chemokine CCL19 / Q000235:genetics / Q000276:immunology; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D054418:Chemokine CCL20 / Q000235:genetics / Q000276:immunology; D054407:Chemokine CCL4 / Q000235:genetics / Q000276:immunology; D054410:Chemokine CCL7 / Q000235:genetics / Q000276:immunology; D002648:Child; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology* / Q000473:pathology / Q000821:virology; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000821:virology; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008168:Lung / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D051379:Mice; D010047:Ovalbumin; D012229:Rhinovirus / Q000472:pathogenicity / Q000502:physiology*; D018418:Th2 Cells / Q000276:immunology; D000097382:CD68 Molecule
chemical_list: D057134:Antibodies, Neutralizing; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D054415:Chemokine CCL19; D018932:Chemokine CCL2; D054418:Chemokine CCL20; D054407:Chemokine CCL4; D054410:Chemokine CCL7; D018793:Interleukin-13; D015847:Interleukin-4; D010047:Ovalbumin; C493447:CCL20 protein, mouse; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C515461:Ccl19 protein, mouse; C491768:Ccl2 protein, mouse; C515451:Ccl7 protein, mouse