title: IL-17 Receptor Signaling in the Lung Epithelium Is Required for Mucosal Chemokine Gradients and Pulmonary Host Defense against K. pneumoniae.
abstract: The cytokine IL-17, and signaling via its heterodimeric IL-17RA/IL-17RC receptor, is critical for host defense against extracellular bacterial and fungal pathogens. Polarized lung epithelial cells express IL-17RA and IL-17RC basolaterally. However, their contribution to IL-17-dependent pulmonary defenses in vivo remains to be determined. To address this, we generated mice with conditional deletion of Il17ra or Il17rc in Scgb1a1-expressing club cells, a major component of the murine bronchiolar epithelium. These mice displayed an impaired ability to recruit neutrophils into the airway lumen in response to IL-17, a defect in bacterial clearance upon mucosal challenge with the pulmonary pathogen Klebsiella pneumoniae, and substantially reduced epithelial expression of the chemokine Cxcl5. Neutrophil recruitment and bacterial clearance were restored by intranasal administration of recombinant CXCL5. Our data show that IL-17R signaling in the lung epithelium plays a critical role in establishing chemokine gradients that are essential for mucosal immunity against pulmonary bacterial pathogens.
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
authors.forename: Kong
authors.initials: K
authors.lastname: Chen
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Eddens
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
authors.forename: Giraldina
authors.initials: G
authors.lastname: Trevejo-Nunez
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Way
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
authors.forename: Waleed
authors.initials: W
authors.lastname: Elsegeiny
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Ricks
authors.affiliation: Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Abhishek V
authors.initials: AV
authors.lastname: Garg
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Erb
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
authors.forename: Meihua
authors.initials: M
authors.lastname: Bo
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Janet S
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gaffen
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA. Electronic address: jay.kolls@chp.edu.
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
mesh_terms: D000818:Animals; D018925:Chemokines / Q000378:metabolism*; D004195:Disease Models, Animal; D007710:Klebsiella Infections / Q000276:immunology*; D007711:Klebsiella pneumoniae / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D018410:Pneumonia, Bacterial / Q000276:immunology; D053722:Receptors, Interleukin-17 / Q000172:deficiency / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000276:immunology*; D015398:Signal Transduction
chemical_list: D018925:Chemokines; D053722:Receptors, Interleukin-17