Alveolar epithelial cells orchestrate DC function in murine viral pneumonia

• Published in: The Journal of clinical investigation 2012-10, Vol.122 (10), p.3652-3664
• Main Authors: Unkel, Barbara, Hoegner, Katrin, Clausen, Björn E, Lewe-Schlosser, Peter, Bodner, Johannes, Gattenloehner, Stefan, Janßen, Hermann, Seeger, Werner, Lohmeyer, Juergen, Herold, Susanne
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - analysis; Antigens, Surface - genetics; Biomedical research; Bone Marrow Transplantation; Cells, Cultured - immunology; Cells, Cultured - virology; Dendritic cells; Dendritic Cells - physiology; Development and progression; Epithelial cells; Epithelial Cells - physiology; Granulocyte-Macrophage Colony-Stimulating Factor - administration & dosage; Granulocyte-Macrophage Colony-Stimulating Factor - biosynthesis; Granulocyte-Macrophage Colony-Stimulating Factor - secretion; Humans; Infections; Influenza; Influenza A Virus, H1N1 Subtype - isolation & purification; Influenza, Human - immunology; Influenza, Human - pathology; Instillation, Drug; Integrin alpha Chains - analysis; Lectins, C-Type - genetics; Lung - immunology; Lung - virology; Lymphatic system; Mannose-Binding Lectins - genetics; Mice; Mice, Inbred C57BL; Mice, Transgenic; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - pathology; Physiological aspects; Pneumonia; Pneumonia, Viral - immunology; Pneumonia, Viral - pathology; Pulmonary Alveoli - immunology; Pulmonary Alveoli - pathology; Radiation Chimera; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - physiology; Risk factors; Specific Pathogen-Free Organisms; Trachea; Viral infections; Viral pneumonia
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI62139

Influenza viruses (IVs) cause pneumonia in humans with progression to lung failure. Pulmonary DCs are key players in the antiviral immune response, which is crucial to restore alveolar barrier function. The mechanisms of expansion and activation of pulmonary DC populations in lung infection remain widely elusive. Using mouse BM chimeric and cell-specific depletion approaches, we demonstrated that alveolar epithelial cell (AEC) GM-CSF mediates recovery from IV-induced injury by affecting lung DC function. Epithelial GM-CSF induced the recruitment of CD11b+ and monocyte-derived DCs. GM-CSF was also required for the presence of CD103+ DCs in the lung parenchyma at baseline and for their sufficient activation and migration to the draining mediastinal lymph nodes (MLNs) during IV infection. These activated CD103+ DCs were indispensable for sufficient clearance of IVs by CD8+ T cells and for recovery from IV-induced lung injury. Moreover, GM-CSF applied intratracheally activated CD103+ DCs, inducing increased migration to MLNs, enhanced viral clearance, and attenuated lung injury. Together, our data reveal that GM-CSF-dependent cross-talk between IV-infected AECs and CD103+ DCs is crucial for effective viral clearance and recovery from injury, which has potential implications for GM-CSF treatment in severe IV pneumonia.