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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

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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 1

NKAα1 protein on the plasma membrane is decreased in a murine model of severe IAV infection.

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NKAα1 protein on the plasma membrane is decreased in a murine model of s...
(A) Representative sections of n = 3 murine lungs d7 after PBS (ctrl) (left panel) or 500 pfu PR8 (IAV) inoculation in vivo, stained sequentially with anti-NKAα1 antibody (red) and DAPI (blue), followed by H&E staining. Sections of IAV-infected mice were taken from highly inflammatory (middle panel) and less inflammatory regions (right panel). Scale bars: 50 μm; arrows mark edematous regions. (B and C) Arterial partial pressure of oxygen (pO2) (B) and in vivo AFC measurements (C) d7 pi after inoculation of PBS or PR8. (D) Gating strategy showing representative dot plots for live cells (7AAD–), epithelial cells (EpCAM+), and representative histograms of NKAα1+ staining or the respective IgG control from murine AEC cultures. SSC, side scatter. (E and F) Densitometric quantification of immunoblots of NKAα1 in relation to β-actin at the indicated time points in total cell lysates of mAEC (E) or hAEC (F) inoculated in vitro with PBS or PR8 for 24 hours. (G and I) Relative MFI of NKAα1 detected by FACS on live mAEC (G) or hAEC (I) treated in vitro with PBS (ctrl) or PR8 (IAV) at MOI 0.1 for 24 or 16 hours, respectively. (H and J) Densitometric analysis of NKAα1 expression in comparison to the housekeeping protein glucose transporter 1 (Glut1) within the cell surface fraction of PR8-infected mAEC at the indicated time points (H) or hAEC 16h pi (I). Values of PBS-treated control conditions were normalized to 1. Representative blots and bar graphs or dot plots show means ±SEM of 7–9 independent experiments for B, C, E, F, and H and 5–6 independent experiments for G, I, and J. Statistical significance was analyzed by unpaired Student’s t test (B, F, G, I, and J) or by 1-way ANOVA and post-hoc Tukey (C, E, and H). *P < 0.05; **P < 0.01; ***P < 0.005.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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