Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection

• Published in: The Journal of clinical investigation Vol. 126; no. 4; pp. 1566 - 1580
• Main Authors: Peteranderl, Christin, Morales-Nebreda, Luisa, Selvakumar, Balachandar, Lecuona, Emilia, Vadász, István, Morty, Rory E, Schmoldt, Carole, Bespalowa, Julia, Wolff, Thorsten, Pleschka, Stephan, Mayer, Konstantin, Gattenloehner, Stefan, Fink, Ludger, Lohmeyer, Juergen, Seeger, Werner, Sznajder, Jacob I, Mutlu, Gökhan M, Budinger, G R Scott, Herold, Susanne
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.04.2016
• Subjects: Adenosine triphosphatase; Animals; Biomedical research; Communications networks; Development and progression; Edema; Flow cytometry; Gene expression; Genetic aspects; Humans; Infections; Influenza; Influenza A virus - immunology; Interferon Type I - immunology; Lung diseases; Macrophages, Alveolar - immunology; Macrophages, Alveolar - pathology; Mice; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - pathology; Paracrine Communication - immunology; Physiological aspects; Properties; Proteins; Pulmonary Alveoli - pathology; Pulmonary Edema - immunology; Pulmonary Edema - pathology; Respiratory distress syndrome; Respiratory Distress Syndrome, Adult - immunology; Respiratory Distress Syndrome, Adult - pathology; Respiratory Mucosa - immunology; Respiratory Mucosa - pathology; Rodents; Sodium; Sodium-Potassium-Exchanging ATPase - immunology; TNF-Related Apoptosis-Inducing Ligand - immunology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci83931

Influenza A viruses (IAV) can cause lung injury and acute respiratory distress syndrome (ARDS), which is characterized by accumulation of excessive fluid (edema) in the alveolar airspaces and leads to hypoxemia and death if not corrected. Clearance of excess edema fluid is driven mostly by the alveolar epithelial Na,K-ATPase and is crucial for survival of patients with ARDS. We therefore investigated whether IAV infection alters Na,K-ATPase expression and function in alveolar epithelial cells (AECs) and the ability of the lung to clear edema. IAV infection reduced Na,K-ATPase in the plasma membrane of human and murine AECs and in distal lung epithelium of infected mice. Moreover, induced Na,K-ATPase improved alveolar fluid clearance (AFC) in IAV-infected mice. We identified a paracrine cell communication network between infected and noninfected AECs and alveolar macrophages that leads to decreased alveolar epithelial Na,K-ATPase function and plasma membrane abundance and inhibition of AFC. We determined that the IAV-induced reduction of Na,K-ATPase is mediated by a host signaling pathway that involves epithelial type I IFN and an IFN-dependent elevation of macrophage TNF-related apoptosis-inducing ligand (TRAIL). Our data reveal that interruption of this cellular crosstalk improves edema resolution, which is of biologic and clinical importance to patients with IAV-induced lung injury.