title: Apoptotic cell clearance by bronchial epithelial cells critically influences airway inflammation.
abstract: Lung epithelial cells can influence immune responses to airway allergens. Airway epithelial cells also undergo apoptosis after encountering environmental allergens; yet, relatively little is known about how these are cleared, and their effect on airway inflammation. Here we show that airway epithelial cells efficiently engulf apoptotic epithelial cells and secrete anti-inflammatory cytokines, dependent upon intracellular signalling by the small GTPase Rac1. Inducible deletion of Rac1 expression specifically in airway epithelial cells in a mouse model resulted in defective engulfment by epithelial cells and aberrant anti-inflammatory cytokine production. Intranasal priming and challenge of these mice with house dust mite extract or ovalbumin as allergens led to exacerbated inflammation, augmented Th2 cytokines and airway hyper-responsiveness, with decreased interleukin (IL)-10 in bronchial lavages. Rac1-deficient epithelial cells produced much higher IL-33 upon allergen or apoptotic cell encounter, with increased numbers of nuocyte-like cells. Administration of exogenous IL-10 'rescued' the airway inflammation phenotype in Rac1-deficient mice, with decreased IL-33. Collectively, these genetic and functional studies suggest a new role for Rac1-dependent engulfment by airway epithelial cells and in establishing the anti-inflammatory environment, and that defects in cell clearance in the airways could contribute to inflammatory responses towards common allergens.
authors.affiliation: Carter Immunology Center, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Ignacio J
authors.initials: IJ
authors.lastname: Juncadella
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kadl
authors.forename: Ashish K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Yun M
authors.initials: YM
authors.lastname: Shim
authors.forename: Amelia
authors.initials: A
authors.lastname: Hochreiter-Hufford
authors.forename: Larry
authors.initials: L
authors.lastname: Borish
authors.forename: Kodi S
authors.initials: KS
authors.lastname: Ravichandran
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D017209:Apoptosis; D001980:Bronchi / Q000166:cytology* / Q000276:immunology / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D004391:Dust / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology / Q000502:physiology*; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000473:pathology*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D000067596:Interleukin-33; D007378:Interleukins / Q000096:biosynthesis / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology*; D051379:Mice; D010047:Ovalbumin / Q000276:immunology; D010587:Phagocytosis; D039981:Pyroglyphidae / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000473:pathology*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation; D020830:rac1 GTP-Binding Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D000485:Allergens; D004391:Dust; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D016753:Interleukin-10; D010047:Ovalbumin; D020830:rac1 GTP-Binding Protein