Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection
Christin Peteranderl, … , G.R. Scott Budinger, Susanne Herold
Christin Peteranderl, … , G.R. Scott Budinger, Susanne Herold
Published March 21, 2016
Citation Information: J Clin Invest. 2016;126(4):1566-1580. https://doi.org/10.1172/JCI83931.
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Research Article Infectious disease Pulmonology Article has an altmetric score of 7

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

Christin Peteranderl, Luisa Morales-Nebreda, Balachandar Selvakumar, Emilia Lecuona, István Vadász, Rory E. Morty, Carole Schmoldt, Julia Bespalowa, Thorsten Wolff, Stephan Pleschka, Konstantin Mayer, Stefan Gattenloehner, Ludger Fink, Juergen Lohmeyer, Werner Seeger, Jacob I. Sznajder, Gökhan M. Mutlu, G.R. Scott Budinger, Susanne Herold

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Figure 7

IAV-induced reduction of epithelial NKAα1 surface expression and AFC capacity require the presence of IFNAR and macrophage-released TRAIL in vivo.

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IAV-induced reduction of epithelial NKAα1 surface expression and AFC cap...
(A and B) Flow cytometric analysis of NKAα1 subunit expression on EpCAM+ epithelial cells from distal lung homogenate. (C and D) In vivo measurements of AFC rates over a time interval of 30 minutes. (A and C) WT, Ifnar–/–, or Trail–/– mice were inoculated with PBS (ctrl) or PR8 (IAV) and sacrificed d7 pi. (B and D) Ccr2–/– mice were inoculated with PR8 (IAV) and sacrificed d7 pi without further intervention (Ccr2–/–) or after intratracheal transfer of flow-sorted alveolar BMM from d7 infected WT (WT to Ccr2–/–) or Trail–/– (Trail–/– to Ccr2–/–) mice at d3 pi. Viral loads were not significantly altered between experimental groups (data not shown). Graphs show single data points plus means ±SEM of 5–10 independent experiments for A and B and 4–6 independent experiments for C and D. Data sets depicting control conditions are similar to Figure 1C (AFC) and Figure 3A (NKAα1 expression). Nonbracketed asterisk indicate statistical significance to control conditions. Statistical significance was analyzed by unpaired Student’s t test (B) or by 1-way ANOVA and post-hoc Tukey. ***P < 0.005.