title: Distinct Tlr4-expressing cell compartments control neutrophilic and eosinophilic airway inflammation.
abstract: Allergic asthma is a chronic, inflammatory lung disease. Some forms of allergic asthma are characterized by T helper type 2 (Th2)-driven eosinophilia, whereas others are distinguished by Th17-driven neutrophilia. Stimulation of Toll-like receptor 4 (TLR4) on hematopoietic and airway epithelial cells (AECs) contributes to the inflammatory response to lipopolysaccharide (LPS) and allergens, but the specific contribution of TLR4 in these cell compartments to airway inflammatory responses remains poorly understood. We used novel, conditionally mutant Tlr4(fl/fl) mice to define the relative contributions of AEC and hematopoietic cell Tlr4 expression to LPS- and allergen-induced airway inflammation. We found that Tlr4 expression by hematopoietic cells is critical for neutrophilic airway inflammation following LPS exposure and for Th17-driven neutrophilic responses to the house dust mite (HDM) lysates and ovalbumin (OVA). Conversely, Tlr4 expression by AECs was found to be important for robust eosinophilic airway inflammation following sensitization and challenge with these same allergens. Thus, Tlr4 expression by hematopoietic and airway epithelial cells controls distinct arms of the immune response to inhaled allergens.
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: McAlees
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Whitehead
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
authors.forename: I T W
authors.initials: IT
authors.lastname: Harley
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
authors.forename: M
authors.initials: M
authors.lastname: Cappelletti
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Rewerts
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Holdcroft
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
authors.forename: S
authors.initials: S
authors.lastname: Divanovic
authors.affiliation: 1] Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, USA [2] Present address: Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Wills-Karp
authors.affiliation: 1] Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, USA [2] Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio, USA [3] Department of Internal Medicine, Division of Allergy, Immunology and Rheumatology, University of Cincinnati School of Medicine, Cincinnati, Ohio, USA.
authors.forename: F D
authors.initials: FD
authors.lastname: Finkelman
authors.affiliation: 1] Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, USA [2] Bill & Melinda Gates Foundation, Seattle, WA, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Karp
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
authors.forename: D N
authors.initials: DN
authors.lastname: Cook
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism; D015870:Gene Expression; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D039981:Pyroglyphidae / Q000276:immunology; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4