title: Alveolar epithelial cells direct monocyte transepithelial migration upon influenza virus infection: impact of chemokines and adhesion molecules.
abstract: Influenza A virus pneumonia is characterized by severe lung injury and high mortality. Early infection elicits a strong recruitment of monocytes from the peripheral blood across the endo-/epithelial barrier into the alveolar air space. However, it is currently unclear which of the infected resident lung cell populations, alveolar epithelial cells or alveolar macrophages, elicit monocyte recruitment during influenza A virus infection. In the current study, we investigated whether influenza A virus infection of primary alveolar epithelial cells and resident alveolar macrophages would elicit a basal-to-apical monocyte transepithelial migration in vitro. We found that infection of alveolar epithelial cells with the mouse-adapted influenza A virus strain PR/8 strongly induced the release of monocyte chemoattractants CCL2 and CCL5 followed by a strong monocyte transepithelial migration, and this monocytic response was strictly dependent on monocyte CCR2 but not CCR5 chemokine receptor expression. Analysis of the adhesion molecule pathways demonstrated a role of ICAM-1, VCAM-1, integrin-associated protein (CD47), and junctional adhesion molecule-c on the epithelial cell surface interacting with monocyte beta(1) and beta(2) integrins and integrin-associated protein in the monocyte transmigration process. Importantly, addition of influenza A virus-infected alveolar macrophages further enhanced monocyte transmigration across virus-infected epithelium in a TNF-alpha-dependent manner. Collectively, the data show an active role for virus-infected alveolar epithelium in the regulation of CCL2/CCR2-dependent monocyte transepithelial migration during influenza infection that is essentially dependent on both classical beta(1) and beta(2) integrins but also junctional adhesion molecule pathways.
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.
authors.forename: Susanne
authors.initials: S
authors.lastname: Herold
authors.forename: Werner
authors.initials: W
authors.lastname: von Wulffen
authors.forename: Mirko
authors.initials: M
authors.lastname: Steinmueller
authors.forename: Stephan
authors.initials: S
authors.lastname: Pleschka
authors.forename: William A
authors.initials: WA
authors.lastname: Kuziel
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
authors.forename: Mrigank
authors.initials: M
authors.lastname: Srivastava
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Ulrich A
authors.initials: UA
authors.lastname: Maus
authors.forename: Juergen
authors.initials: J
authors.lastname: Lohmeyer
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000502:physiology*; D002450:Cell Communication / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018925:Chemokines / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004847:Epithelial Cells / Q000737:chemistry / Q000276:immunology* / Q000821:virology; D005260:Female; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000737:chemistry / Q000276:immunology* / Q000821:virology; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins / Q000032:analysis; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000276:immunology* / Q000821:virology; D016601:RNA-Binding Proteins / Q000032:analysis; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology; D014758:Viral Core Proteins / Q000032:analysis
chemical_list: C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D018925:Chemokines; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins; D016601:RNA-Binding Proteins; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D014758:Viral Core Proteins