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Macrophage-expressed IFN-β contributes to apoptotic alveolar epithelial cell injury in severe influenza virus pneumonia.

Högner K, Wolff T, Pleschka S, Plog S, Gruber AD, Kalinke U, Walmrath HD, Bodner J, Gattenlöhner S, Lewe-Schlosser P, Matrosovich M, Seeger W, Lohmeyer J, Herold S - PLoS Pathog. (2013)

Bottom Line: Bone marrow chimeric mice lacking these signalling mediators in resident and lung-recruited AM and mice subjected to alveolar neutralization of IFN-β and TRAIL displayed reduced alveolar epithelial cell apoptosis and attenuated lung injury during severe IV pneumonia.Together, we demonstrate that macrophage-released type I IFNs, apart from their well-known anti-viral properties, contribute to IV-induced AEC damage and lung injury by autocrine induction of the pro-apoptotic factor TRAIL.Our data suggest that therapeutic targeting of the macrophage IFN-β-TRAIL axis might represent a promising strategy to attenuate IV-induced acute lung injury.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine II, University of Giessen Lung Center, Giessen, Germany.

ABSTRACT
Influenza viruses (IV) cause pneumonia in humans with progression to lung failure and fatal outcome. Dysregulated release of cytokines including type I interferons (IFNs) has been attributed a crucial role in immune-mediated pulmonary injury during severe IV infection. Using ex vivo and in vivo IV infection models, we demonstrate that alveolar macrophage (AM)-expressed IFN-β significantly contributes to IV-induced alveolar epithelial cell (AEC) injury by autocrine induction of the pro-apoptotic factor TNF-related apoptosis-inducing ligand (TRAIL). Of note, TRAIL was highly upregulated in and released from AM of patients with pandemic H1N1 IV-induced acute lung injury. Elucidating the cell-specific underlying signalling pathways revealed that IV infection induced IFN-β release in AM in a protein kinase R- (PKR-) and NF-κB-dependent way. Bone marrow chimeric mice lacking these signalling mediators in resident and lung-recruited AM and mice subjected to alveolar neutralization of IFN-β and TRAIL displayed reduced alveolar epithelial cell apoptosis and attenuated lung injury during severe IV pneumonia. Together, we demonstrate that macrophage-released type I IFNs, apart from their well-known anti-viral properties, contribute to IV-induced AEC damage and lung injury by autocrine induction of the pro-apoptotic factor TRAIL. Our data suggest that therapeutic targeting of the macrophage IFN-β-TRAIL axis might represent a promising strategy to attenuate IV-induced acute lung injury.

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Related in: MedlinePlus

Proposed model of IFN-β mediated pro-apoptotic AM-AEC cross-talk in IV-induced lung injury.IFN-β is released from IV-infected AM in a PKR- and NF-κB-dependent way and induces expression and release of macrophage TRAIL via autocrine IFNAR activation. Macrophage TRAIL induces AEC apoptosis via its receptor DR5 which is constitutively expressed on non-infected and upregulated on IV-infected AEC. Through this signalling cascade, IFN-β significantly contributes to AEC damage and lung injury during severe IV pneumonia. IV, influenza virus.
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ppat-1003188-g009: Proposed model of IFN-β mediated pro-apoptotic AM-AEC cross-talk in IV-induced lung injury.IFN-β is released from IV-infected AM in a PKR- and NF-κB-dependent way and induces expression and release of macrophage TRAIL via autocrine IFNAR activation. Macrophage TRAIL induces AEC apoptosis via its receptor DR5 which is constitutively expressed on non-infected and upregulated on IV-infected AEC. Through this signalling cascade, IFN-β significantly contributes to AEC damage and lung injury during severe IV pneumonia. IV, influenza virus.

Mentions: IV pneumonia is characterized by infection of distal lung epithelial cells and resident macrophages and frequently progresses to acute lung injury/ARDS with poor outcome. Rapid onset of effective host defense strategies is therefore crucial for recovery from IV-induced lung damage. On the other side, an exaggerated inflammatory response will add substantial tissue injury to virus-induced cytopathic damage. This study elucidates a previously unrecognized pathway of cytokine-mediated epithelial injury and highlights the IV-infected alveolar macrophage as key player in this scenario. We demonstrate that IFN-β, induced in IV-infected AM through a PKR-NF-κB-dependent pathway, induces expression and release of the pro-apoptotic ligand TRAIL by autocrine IFNAR activation, and thereby significantly contributes to IV-induced apoptotic tissue injury (Fig. 9).


Macrophage-expressed IFN-β contributes to apoptotic alveolar epithelial cell injury in severe influenza virus pneumonia.

Högner K, Wolff T, Pleschka S, Plog S, Gruber AD, Kalinke U, Walmrath HD, Bodner J, Gattenlöhner S, Lewe-Schlosser P, Matrosovich M, Seeger W, Lohmeyer J, Herold S - PLoS Pathog. (2013)

Proposed model of IFN-β mediated pro-apoptotic AM-AEC cross-talk in IV-induced lung injury.IFN-β is released from IV-infected AM in a PKR- and NF-κB-dependent way and induces expression and release of macrophage TRAIL via autocrine IFNAR activation. Macrophage TRAIL induces AEC apoptosis via its receptor DR5 which is constitutively expressed on non-infected and upregulated on IV-infected AEC. Through this signalling cascade, IFN-β significantly contributes to AEC damage and lung injury during severe IV pneumonia. IV, influenza virus.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585175&req=5

ppat-1003188-g009: Proposed model of IFN-β mediated pro-apoptotic AM-AEC cross-talk in IV-induced lung injury.IFN-β is released from IV-infected AM in a PKR- and NF-κB-dependent way and induces expression and release of macrophage TRAIL via autocrine IFNAR activation. Macrophage TRAIL induces AEC apoptosis via its receptor DR5 which is constitutively expressed on non-infected and upregulated on IV-infected AEC. Through this signalling cascade, IFN-β significantly contributes to AEC damage and lung injury during severe IV pneumonia. IV, influenza virus.
Mentions: IV pneumonia is characterized by infection of distal lung epithelial cells and resident macrophages and frequently progresses to acute lung injury/ARDS with poor outcome. Rapid onset of effective host defense strategies is therefore crucial for recovery from IV-induced lung damage. On the other side, an exaggerated inflammatory response will add substantial tissue injury to virus-induced cytopathic damage. This study elucidates a previously unrecognized pathway of cytokine-mediated epithelial injury and highlights the IV-infected alveolar macrophage as key player in this scenario. We demonstrate that IFN-β, induced in IV-infected AM through a PKR-NF-κB-dependent pathway, induces expression and release of the pro-apoptotic ligand TRAIL by autocrine IFNAR activation, and thereby significantly contributes to IV-induced apoptotic tissue injury (Fig. 9).

Bottom Line: Bone marrow chimeric mice lacking these signalling mediators in resident and lung-recruited AM and mice subjected to alveolar neutralization of IFN-β and TRAIL displayed reduced alveolar epithelial cell apoptosis and attenuated lung injury during severe IV pneumonia.Together, we demonstrate that macrophage-released type I IFNs, apart from their well-known anti-viral properties, contribute to IV-induced AEC damage and lung injury by autocrine induction of the pro-apoptotic factor TRAIL.Our data suggest that therapeutic targeting of the macrophage IFN-β-TRAIL axis might represent a promising strategy to attenuate IV-induced acute lung injury.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine II, University of Giessen Lung Center, Giessen, Germany.

ABSTRACT
Influenza viruses (IV) cause pneumonia in humans with progression to lung failure and fatal outcome. Dysregulated release of cytokines including type I interferons (IFNs) has been attributed a crucial role in immune-mediated pulmonary injury during severe IV infection. Using ex vivo and in vivo IV infection models, we demonstrate that alveolar macrophage (AM)-expressed IFN-β significantly contributes to IV-induced alveolar epithelial cell (AEC) injury by autocrine induction of the pro-apoptotic factor TNF-related apoptosis-inducing ligand (TRAIL). Of note, TRAIL was highly upregulated in and released from AM of patients with pandemic H1N1 IV-induced acute lung injury. Elucidating the cell-specific underlying signalling pathways revealed that IV infection induced IFN-β release in AM in a protein kinase R- (PKR-) and NF-κB-dependent way. Bone marrow chimeric mice lacking these signalling mediators in resident and lung-recruited AM and mice subjected to alveolar neutralization of IFN-β and TRAIL displayed reduced alveolar epithelial cell apoptosis and attenuated lung injury during severe IV pneumonia. Together, we demonstrate that macrophage-released type I IFNs, apart from their well-known anti-viral properties, contribute to IV-induced AEC damage and lung injury by autocrine induction of the pro-apoptotic factor TRAIL. Our data suggest that therapeutic targeting of the macrophage IFN-β-TRAIL axis might represent a promising strategy to attenuate IV-induced acute lung injury.

Show MeSH
Related in: MedlinePlus