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

Abstract

BackgroundInfluenza 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.MethodsMice 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.ResultsSupra-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).ConclusionsOur 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.Electronic supplementary materialThe online version of this article (10.1186/s12931-017-0708-5) contains supplementary material, which is available to authorized users.

The immune response to influenza in older humans: beyond immune senescence

“…We are unaware of any studies that have investigated changes in human macrophage phagocytic function with age, but a relatively recent study did find that the uptake of opsonized bacteria was significantly reduced in CD14+ monocytes from older adults [78]. This becomes important as influenza infection has been shown to induce inflammation causing lung injury and life-threatening pneumonia, either primary viral pneumonia or secondary bacterial infection [79]. This acute inflammation in response to influenza infection is mediated by lung monocytes and monocytederived dendritic cells that are involved in the detection and clearance of influenza virus and influenza pathogenesis in the lungs [80].…”

Prion protein signaling induces M2 macrophage polarization and protects from lethal influenza infection in mice

“…Several reports indicate that M2 macrophages could be therapeutically beneficial for IAV infection. Mice intranasally administered with exogenous M2 macrophages or transgenically expressing granulocyte-macrophage colony-stimulating factor in lung epithelial cells to increase M2 macrophages were shown to display better clinical scores than control mice after infection with IAV [ 30 , 31 ]. It is thus likely that the anti-PrP mAb-induced M2 macrophage generation through SFK activation is the underlying mechanism for the anti-PrP mAb-induced protective activity of PrP C against IAV infection.…”

Direct Effects of Gm-CSF on the Functions of Human Monocytes/Macrophages

“…Считается, что функциональный баланс между мигрировавшими M1 Мф и резидентными M2 Мф в значительной, если не в определяющей степени, определяет течение воспалительного процесса [12]. Однако, согласно недавно опубликованным данным, прямое ингаляционное воздействие GM-CSF на легочные Мф может придавать им антивоспалительные свойства [11]. Показано, что продукция GM-CSF в опухолевых очагах может способствовать альтернативной активации Мф, поддерживающей опухолевый рост [23].…”