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

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 effic...

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Bibliographic Details
Published in:	Respiratory research Vol. 19; no. 1; p. 3
Main Authors:	Halstead, E Scott, Umstead, Todd M, Davies, Michael L, Kawasawa, Yuka Imamura, Silveyra, Patricia, Howyrlak, Judie, Yang, Linlin, Guo, Weichao, Hu, Sanmei, Hewage, Eranda Kurundu, Chroneos, Zissis C
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 05-01-2018 BioMed Central BMC
Subjects:	Alveolar Animals Cell Polarity - physiology Development and progression Exudative Female Gene Expression Genetic aspects GM-CSF Granulocyte-macrophage colony stimulating factor Granulocyte-Macrophage Colony-Stimulating Factor - biosynthesis Granulocyte-Macrophage Colony-Stimulating Factor - genetics Influenza Influenza A virus Macrophage Macrophages Macrophages - metabolism Male Mice Mice, Inbred C57BL Mice, Transgenic Monocytes - metabolism Mortality - trends Orthomyxoviridae Infections - metabolism Orthomyxoviridae Infections - mortality Orthomyxoviridae Infections - prevention & control Physiological aspects Pneumonia Prognosis United States Pneumonia Alveolar RNA-seq GM-CSF Influenza Exudative Interferon Macrophage
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Summary:	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. 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. 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). 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1465-993X 1465-9921 1465-993X
DOI:	10.1186/s12931-017-0708-5