title: Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand.
abstract: Mononuclear phagocytes have been attributed a crucial role in the host defense toward influenza virus (IV), but their contribution to influenza-induced lung failure is incompletely understood. We demonstrate for the first time that lung-recruited "exudate" macrophages significantly contribute to alveolar epithelial cell (AEC) apoptosis by the release of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in a murine model of influenza-induced pneumonia. Using CC-chemokine receptor 2-deficient (CCR2(-/-)) mice characterized by defective inflammatory macrophage recruitment, and blocking anti-CCR2 antibodies, we show that exudate macrophage accumulation in the lungs of influenza-infected mice is associated with pronounced AEC apoptosis and increased lung leakage and mortality. Among several proapoptotic mediators analyzed, TRAIL messenger RNA was found to be markedly up-regulated in alveolar exudate macrophages as compared with peripheral blood monocytes. Moreover, among the different alveolar-recruited leukocyte subsets, TRAIL protein was predominantly expressed on macrophages. Finally, abrogation of TRAIL signaling in exudate macrophages resulted in significantly reduced AEC apoptosis, attenuated lung leakage, and increased survival upon IV infection. Collectively, these findings demonstrate a key role for exudate macrophages in the induction of alveolar leakage and mortality in IV pneumonia. Epithelial cell apoptosis induced by TRAIL-expressing macrophages is identified as a major underlying mechanism.
authors.affiliation: University of Giessen Lung Center, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine and Infectious Diseases, Justus-Liebig-University, Giessen, Germany. Susanne.Herold@innere.med.uni-giessen.de
authors.forename: Susanne
authors.initials: S
authors.lastname: Herold
authors.forename: Mirko
authors.initials: M
authors.lastname: Steinmueller
authors.forename: Werner
authors.initials: W
authors.lastname: von Wulffen
authors.forename: Lidija
authors.initials: L
authors.lastname: Cakarova
authors.forename: Ruth
authors.initials: R
authors.lastname: Pinto
authors.forename: Stephan
authors.initials: S
authors.lastname: Pleschka
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
authors.forename: William A
authors.initials: WA
authors.lastname: Kuziel
authors.forename: Nadia
authors.initials: N
authors.lastname: Corazza
authors.forename: Thomas
authors.initials: T
authors.lastname: Brunner
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Juergen
authors.initials: J
authors.lastname: Lohmeyer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002678:Chimera; D006801:Humans; D007251:Influenza, Human / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000502:physiology / Q000821:virology; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009975:Orthomyxoviridae / Q000276:immunology* / Q000472:pathogenicity; D010586:Phagocytes / Q000276:immunology; D011014:Pneumonia / Q000276:immunology* / Q000401:mortality / Q000821:virology; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000276:immunology / Q000473:pathology / Q000821:virology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2; D053221:TNF-Related Apoptosis-Inducing Ligand