Lung epithelial GM-CSF improves host defense function and epithelial repair in influenza virus pneumonia-a new therapeutic strategy?

Barbara Rösler, Susanne Herold, Barbara Rösler, Susanne Herold

Abstract

Influenza viruses (IVs) circulate seasonally and are a common cause of respiratory infections in pediatric and adult patients. Additionally, recurrent pandemics cause massive morbidity and mortality worldwide. Infection may result in rapid progressive viral pneumonia with fatal outcome. Since accurate treatment strategies are still missing, research refocuses attention to lung pathology and cellular crosstalk to develop new therapeutic options.Alveolar epithelial cells (AECs) play an important role in orchestrating the pulmonary antiviral host response. After IV infection they release a cascade of immune mediators, one of which is granulocyte and macrophage colony-stimulating factor (GM-CSF). GM-CSF is known to promote differentiation, activation and mobilization of myeloid cells. In the lung, GM-CSF drives immune functions of alveolar macrophages and dendritic cells (DCs) and also improves epithelial repair processes through direct interaction with AECs. During IV infection, AEC-derived GM-CSF shows a lung-protective effect that is also present after local GM-CSF application. This mini-review provides an overview on GM-CSF-modulated immune responses to IV pneumonia and its therapeutic potential in severe IV pneumonia.

Keywords: AEC; ARDS; GM-CSF; Influenza; Pneumonia; Therapy.

Figures

Fig. 1
Fig. 1
GM-CSF-modulated immune response to IV infection. After pulmonary IV infection GM-CSF is released from AEC II, mediated through HGF/c-Met and TGF-α/EGFR signaling. In an autocrine manner, it stimulates epithelial repair, including epithelial proliferation and barrier restoration. Innate and adaptive immunity are activated, resulting in accelerated viral clearance. Via PU.1, GM-CSF improves AM resistance, maturation, ROS production, and phagocytosis capacity, e.g., by the FcγR-mediated opsonophagocytosis. GM-CSF also stimulates activation and proliferation of DCs, especially CD103+ DCs, and T cells and enhances Ag priming and IV-specific CD8+ T cell recruitment. Altogether AEC GM-CSF leads to increased survival and reduced lung injury. AEC alveolar epithelial cells, Ag antigen, AM alveolar macrophage, c-Met hepatocyte growth factor receptor, DC dendritic cell, EGFR epithelial growth factor receptor, FcγR Fcɣ receptor, GM-CSF granulocyte and macrophage colony stimulating factor, HGF hepatocyte growth factor, PU.1 transcription factor PU.1, ROS reactive oxygen species, TGF-α transcriptional growth factor α

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