TY - JOUR
T1 - Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection
AU - Peteranderl, Christin
AU - Morales-Nebreda, Luisa
AU - Selvakumar, Balachandar
AU - Lecuona, Emilia
AU - Vadász, István
AU - Morty, Rory E.
AU - Schmoldt, Carole
AU - Bespalowa, Julia
AU - Wolff, Thorsten
AU - Pleschka, Stephan
AU - Mayer, Konstantin
AU - Gattenloehner, Stefan
AU - Fink, Ludger
AU - Lohmeyer, Juergen
AU - Seeger, Werner
AU - Sznajder, Jacob I.
AU - Mutlu, Gökhan M.
AU - Budinger, G. R.Scott
AU - Herold, Susanne
N1 - Funding Information:
This study was supported by the German Research Foundation (SFB-TR84 B2, IRTG1062, SFB1021 C05, EXC147 to S. Herold, J. Lohmeyer, W. Seeger, S. Pleschka, and T. Wolff) by the German Federal Ministry of Research and Education ("FluResearchNet" 01 KI 1006M to S. Herold and J. Lohmeyer), and by DZL (to S. Herold, J. Lohmeyer, W. Seeger, I. Vadász, K. Mayer, L. Fink, and R.E. Morty), by ES015024 and ES025644 (to G.M. Mutlu), and by HL-48129 and 71643 (to G.R.S. Budninger and J.I. Sznajder).
PY - 2016/4/1
Y1 - 2016/4/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI83931
DO - 10.1172/JCI83931
M3 - Article
C2 - 26999599
AN - SCOPUS:84964662661
VL - 126
SP - 1566
EP - 1580
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 4
ER -