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Macrophage activation state determines the response to rhinovirus infection in a mouse model of allergic asthma
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-activate...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066837/ https://www.ncbi.nlm.nih.gov/pubmed/24907978 http://dx.doi.org/10.1186/1465-9921-15-63 |
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author | Hong, Jun Young Chung, Yutein Steenrod, Jessica Chen, Qiang Lei, Jing Comstock, Adam T Goldsmith, Adam M Bentley, J Kelley Sajjan, Uma S Hershenson, Marc B |
author_facet | Hong, Jun Young Chung, Yutein Steenrod, Jessica Chen, Qiang Lei, Jing Comstock, Adam T Goldsmith, Adam M Bentley, J Kelley Sajjan, Uma S Hershenson, Marc B |
author_sort | Hong, Jun Young |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4066837 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-40668372014-06-24 Macrophage activation state determines the response to rhinovirus infection in a mouse model of allergic asthma Hong, Jun Young Chung, Yutein Steenrod, Jessica Chen, Qiang Lei, Jing Comstock, Adam T Goldsmith, Adam M Bentley, J Kelley Sajjan, Uma S Hershenson, Marc B Respir Res Research 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. BioMed Central 2014 2014-06-07 /pmc/articles/PMC4066837/ /pubmed/24907978 http://dx.doi.org/10.1186/1465-9921-15-63 Text en Copyright © 2014 Hong et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Hong, Jun Young Chung, Yutein Steenrod, Jessica Chen, Qiang Lei, Jing Comstock, Adam T Goldsmith, Adam M Bentley, J Kelley Sajjan, Uma S Hershenson, Marc B Macrophage activation state determines the response to rhinovirus infection in a mouse model of allergic asthma |
title | Macrophage activation state determines the response to rhinovirus infection in a mouse model of allergic asthma |
title_full | Macrophage activation state determines the response to rhinovirus infection in a mouse model of allergic asthma |
title_fullStr | Macrophage activation state determines the response to rhinovirus infection in a mouse model of allergic asthma |
title_full_unstemmed | Macrophage activation state determines the response to rhinovirus infection in a mouse model of allergic asthma |
title_short | Macrophage activation state determines the response to rhinovirus infection in a mouse model of allergic asthma |
title_sort | macrophage activation state determines the response to rhinovirus infection in a mouse model of allergic asthma |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066837/ https://www.ncbi.nlm.nih.gov/pubmed/24907978 http://dx.doi.org/10.1186/1465-9921-15-63 |
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