title: Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin αvβ8-mediated activation of TGF-β.
abstract: The airway is a primary portal of entry for noxious environmental stimuli that can trigger airway remodeling, which contributes significantly to airway obstruction in chronic obstructive pulmonary disease (COPD) and chronic asthma. Important pathologic components of airway remodeling include fibrosis and abnormal innate and adaptive immune responses. The positioning of fibroblasts in interstitial spaces suggests that they could participate in both fibrosis and chemokine regulation of the trafficking of immune cells such as dendritic cells, which are crucial antigen-presenting cells. However, physiological evidence for this dual role for fibroblasts is lacking. Here, in two physiologically relevant models - conditional deletion in mouse fibroblasts of the TGF-β-activating integrin αvβ8 and neutralization of αvβ8 in human COPD fibroblasts - we have elucidated a mechanism whereby lung fibroblast chemokine secretion directs dendritic cell trafficking, in a manner that is critically dependent on αvβ8-mediated activation of TGF-β by fibroblasts. Our data therefore indicate that fibroblasts have a crucial role in regulating both fibrotic and immune responses in the lung.
authors.affiliation: Department of Pathology, UCSF, San Francisco, California, USA.
authors.forename: Hideya
authors.initials: H
authors.lastname: Kitamura
authors.forename: Stephanie
authors.initials: S
authors.lastname: Cambier
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Somanath
authors.forename: Tyren
authors.initials: T
authors.lastname: Barker
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Minagawa
authors.forename: Jennifer
authors.initials: J
authors.lastname: Markovics
authors.forename: Amanda
authors.initials: A
authors.lastname: Goodsell
authors.forename: Jean
authors.initials: J
authors.lastname: Publicover
authors.forename: Louis
authors.initials: L
authors.lastname: Reichardt
authors.forename: David
authors.initials: D
authors.lastname: Jablons
authors.forename: Paul
authors.initials: P
authors.lastname: Wolters
authors.forename: Arthur
authors.initials: A
authors.lastname: Hill
authors.forename: James D
authors.initials: JD
authors.lastname: Marks
authors.forename: Jianlong
authors.initials: J
authors.lastname: Lou
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Pittet
authors.forename: Jack
authors.initials: J
authors.lastname: Gauldie
authors.forename: Jody Lynn
authors.initials: JL
authors.lastname: Baron
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nishimura
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology; D018925:Chemokines / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005355:Fibrosis / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology / Q000494:pharmacology; D008168:Lung / Q000166:cytology* / Q000276:immunology / Q000473:pathology*; D051379:Mice; D011014:Pneumonia / Q000276:immunology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology*
chemical_list: D018925:Chemokines; D016207:Cytokines; D016023:Integrins; D053583:Interleukin-1beta; D016212:Transforming Growth Factor beta; C403414:integrin alphavbeta8