title: Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection.
abstract: 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.
authors.forename: Christin
authors.initials: C
authors.lastname: Peteranderl
authors.forename: Luisa
authors.initials: L
authors.lastname: Morales-Nebreda
authors.forename: Balachandar
authors.initials: B
authors.lastname: Selvakumar
authors.forename: Emilia
authors.initials: E
authors.lastname: Lecuona
authors.forename: István
authors.initials: I
authors.lastname: Vadász
authors.forename: Rory E
authors.initials: RE
authors.lastname: Morty
authors.forename: Carole
authors.initials: C
authors.lastname: Schmoldt
authors.forename: Julia
authors.initials: J
authors.lastname: Bespalowa
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wolff
authors.forename: Stephan
authors.initials: S
authors.lastname: Pleschka
authors.forename: Konstantin
authors.initials: K
authors.lastname: Mayer
authors.forename: Stefan
authors.initials: S
authors.lastname: Gattenloehner
authors.forename: Ludger
authors.initials: L
authors.lastname: Fink
authors.forename: Juergen
authors.initials: J
authors.lastname: Lohmeyer
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Jacob I
authors.initials: JI
authors.lastname: Sznajder
authors.forename: Gökhan M
authors.initials: GM
authors.lastname: Mutlu
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
authors.forename: Susanne
authors.initials: S
authors.lastname: Herold
mesh_terms: D000818:Animals; D006801:Humans; D009980:Influenza A virus / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000473:pathology; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000473:pathology; D019899:Paracrine Communication / Q000276:immunology*; D011650:Pulmonary Alveoli / Q000473:pathology; D011654:Pulmonary Edema / Q000276:immunology* / Q000473:pathology; D012128:Respiratory Distress Syndrome / Q000276:immunology / Q000473:pathology; D020545:Respiratory Mucosa / Q000276:immunology* / Q000473:pathology; D000254:Sodium-Potassium-Exchanging ATPase / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology*
chemical_list: D007370:Interferon Type I; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase