Macrophage activation state determines the response to rhinovirus infection in a mouse model of allergic asthma

Respiratory Research

Marc B Hershenson²  Uma S Sajjan³  J Kelley Bentley³  Adam M Goldsmith³  Adam T Comstock³  Jing Lei³  Qiang Chen³  Jessica Steenrod³  Yutein Chung³  Jun Young Hong¹ 

[1] Department of Molecular and Integrative Physiology, University of Michigan Medical School, 48109 Ann Arbor, MI, USA;Medical Sciences Research Building II, 1150 W. Medical Center Drive, Ann Arbor, MI, USA;Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, 48109 Ann Arbor, MI, USA

关键词: M2 polarization;    IL-17A;    IL-13;    Exacerbation;    Asthma;   

Others  :  790258
DOI  :  10.1186/1465-9921-15-63

 received in 2014-02-17, accepted in 2014-06-02,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Hong et al.; licensee BioMed Central Ltd.

【 图 表 】

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