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01.12.2018 | Research | Ausgabe 1/2018 Open Access

Respiratory Research 1/2018

GM-CSF overexpression after influenza a virus infection prevents mortality and moderates M1-like airway monocyte/macrophage polarization

Zeitschrift:
Respiratory Research > Ausgabe 1/2018
Autoren:
E. Scott Halstead, Todd M. Umstead, Michael L. Davies, Yuka Imamura Kawasawa, Patricia Silveyra, Judie Howyrlak, Linlin Yang, Weichao Guo, Sanmei Hu, Eranda Kurundu Hewage, Zissis C. Chroneos
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12931-017-0708-5) contains supplementary material, which is available to authorized users.

Abstract

Background

Influenza A viruses cause life-threatening pneumonia and lung injury in the lower respiratory tract. Application of high GM-CSF levels prior to infection has been shown to reduce morbidity and mortality from pathogenic influenza infection in mice, but the mechanisms of protection and treatment efficacy have not been established.

Methods

Mice were infected intranasally with influenza A virus (PR8 strain). Supra-physiologic levels of GM-CSF were induced in the airways using the double transgenic GM-CSF (DTGM) or littermate control mice starting on 3 days post-infection (dpi). Assessment of respiratory mechanical parameters was performed using the flexiVent rodent ventilator. RNA sequence analysis was performed on FACS-sorted airway macrophage subsets at 8 dpi.

Results

Supra-physiologic levels of GM-CSF conferred a survival benefit, arrested the deterioration of lung mechanics, and reduced the abundance of protein exudates in bronchoalveolar (BAL) fluid to near baseline levels. Transcriptome analysis, and subsequent validation ELISA assays, revealed that excess GM-CSF re-directs macrophages from an “M1-like” to a more “M2-like” activation state as revealed by alterations in the ratios of CXCL9 and CCL17 in BAL fluid, respectively. Ingenuity pathway analysis predicted that GM-CSF surplus during IAV infection elicits expression of anti-inflammatory mediators and moderates M1 macrophage pro-inflammatory signaling by Type II interferon (IFN-γ).

Conclusions

Our data indicate that application of high levels of GM-CSF in the lung after influenza A virus infection alters pathogenic “M1-like” macrophage inflammation. These results indicate a possible therapeutic strategy for respiratory virus-associated pneumonia and acute lung injury.
Zusatzmaterial
Additional file 2: Table S2. Multi-parameter flow cytometry was utilized to characterize the alveolar and exudative macrophages as shown in Fig. 4. All monoclonal antibodies were purchased from either AbD Serotec, BD Bioscience or eBioscience, respectively. (TIFF 3075 kb)
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