Abstract
Human rhinovirus (RV) infection is responsible for the majority of virus-induced asthma exacerbations. Using a mouse model of human RV infection, we sought to determine the requirement of CXCR2, the receptor for ELR-positive CXC chemokines, for RV-induced airway neutrophilia and hyperresponsiveness. Wild-type and CXCR2(-/-) mice were inoculated intranasally with RV1B or sham HeLa cell supernatant. Following RV1B infection, CXCR2(-/-) mice showed reduced airway and lung neutrophils and cholinergic responsiveness compared with wild-type mice. Similar results were obtained in mice treated with neutralizing Ab to Ly6G, a neutrophil-depleting Ab. Lungs from RV-infected, CXCR2(-/-) mice showed significantly reduced production of TNF-alpha, MIP-2/CXCL2, and KC/CXCL1 and lower expression of MUC5B compared with RV-treated wild-type mice. The requirement of TNF-alpha for RV1B-induced airway responses was tested using TNFR1(-/-) mice. TNFR1(-/-) animals displayed reduced airway responsiveness to RV1B, even when exogenous MIP-2 was added to the airways. We conclude that CXCR2 is required for RV-induced neutrophilic airway inflammation and that neutrophil TNF-alpha release is required for airway hyperresponsiveness.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Asthma / physiopathology*
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Bronchial Hyperreactivity / immunology*
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Bronchial Hyperreactivity / metabolism
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Bronchial Hyperreactivity / virology
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Chemokine CXCL1 / immunology
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Chemokine CXCL1 / metabolism
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Chemokine CXCL2 / immunology
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Chemokine CXCL2 / metabolism
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Disease Models, Animal
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Humans
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Lung / immunology
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Lung / metabolism
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Lung / pathology
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Lung / virology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Mucin-5B / immunology
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Mucin-5B / metabolism
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Neutrophils / immunology
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Neutrophils / metabolism
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Neutrophils / virology
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Picornaviridae Infections / immunology*
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Picornaviridae Infections / metabolism
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Picornaviridae Infections / virology
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RNA, Viral / analysis
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Receptors, Interleukin-8B / genetics
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Receptors, Interleukin-8B / immunology*
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Receptors, Interleukin-8B / metabolism
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Receptors, Tumor Necrosis Factor, Type I / genetics
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Receptors, Tumor Necrosis Factor, Type I / immunology
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Receptors, Tumor Necrosis Factor, Type I / metabolism
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Rhinovirus*
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Tumor Necrosis Factor-alpha / immunology
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Chemokine CXCL1
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Chemokine CXCL2
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Cxcl1 protein, mouse
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Cxcl2 protein, mouse
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Muc5b protein, mouse
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Mucin-5B
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RNA, Viral
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Receptors, Interleukin-8B
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Receptors, Tumor Necrosis Factor, Type I
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Tnfrsf1a protein, mouse
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Tumor Necrosis Factor-alpha