title: TGF-β-Dependent Dendritic Cell Chemokinesis in Murine Models of Airway Disease.
abstract: Small airway chronic inflammation is a major pathologic feature of chronic obstructive pulmonary disease (COPD) and is refractory to current treatments. Dendritic cells (DCs) accumulate around small airways in COPD. DCs are critical mediators of Ag surveillance and Ag presentation and amplify adaptive immune responses. How DCs accumulate around airways remains largely unknown. We use 2-photon DC imaging of living murine lung sections to directly visualize the dynamic movement of living DCs around airways in response to either soluble mediators (IL-1β) or environmental stimuli (cigarette smoke or TLR3 ligands) implicated in COPD pathogenesis. We find that DCs accumulate around murine airways primarily by increasing velocity (chemokinesis) rather than directional migration (chemotaxis) in response to all three stimuli. DC accumulation maximally occurs in a specific zone located 26-50 μm from small airways, which overlaps with zones of maximal DC velocity. Our data suggest that increased accumulation of DCs around airways results from increased numbers of highly chemokinetic DCs entering the lung from the circulation with balanced rates of immigration and emigration. Increases in DC accumulation and chemokinesis are partially dependent on ccr6, a crucial DC chemokine receptor, and fibroblast expression of the integrin αvβ8, a critical activator of TGF-β. αvβ8-Mediated TGF-β activation is known to enhance IL-1β-dependent fibroblast expression of the only known endogenous ccr6 chemokine ligand, ccl20. Taken together, these data suggest a mechanism by which αvβ8, ccl20, and ccr6 interact to lead to DC accumulation around airways in response to COPD-relevant stimuli.
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94110;
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94110;
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Yanagisawa
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94110;
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Minagawa
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94110;
authors.forename: Debasish
authors.initials: D
authors.lastname: Sen
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94110;
authors.forename: Royce
authors.initials: R
authors.lastname: Ma
authors.affiliation: Respiratory, Inflammation, and Autoimmunity, MedImmune, Gaithersburg, MD 20878 and Cambridge CB21 6GH, United Kingdom;
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Murray
authors.affiliation: Respiratory, Inflammation, and Autoimmunity, MedImmune, Gaithersburg, MD 20878 and Cambridge CB21 6GH, United Kingdom;
authors.forename: Ping
authors.initials: P
authors.lastname: Tsui
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94110; and.
authors.forename: Jianlong
authors.initials: J
authors.lastname: Lou
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94110; and.
authors.forename: James D
authors.initials: JD
authors.lastname: Marks
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94110.
authors.forename: Jody L
authors.initials: JL
authors.lastname: Baron
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94110;
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Krummel
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94110; stephen.nishimura@ucsf.edu.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nishimura
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000818:Animals; D002465:Cell Movement / Q000276:immunology; D054418:Chemokine CCL20 / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000276:immunology; D005347:Fibroblasts / Q000276:immunology; D016023:Integrins / Q000096:biosynthesis / Q000276:immunology*; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000276:immunology*; D008168:Lung / Q000000981:diagnostic imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011070:Poly I-C / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology* / Q000473:pathology; D011859:Radiography; D054399:Receptors, CCR6 / Q000235:genetics / Q000276:immunology; D012906:Smoke / Q000009:adverse effects; D051196:Toll-Like Receptor 3; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000378:metabolism
chemical_list: C493447:CCL20 protein, mouse; C498126:CCR6 protein, mouse; D054418:Chemokine CCL20; C587672:IL1B protein, mouse; D016023:Integrins; D053583:Interleukin-1beta; D054399:Receptors, CCR6; D012906:Smoke; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D016212:Transforming Growth Factor beta; C403414:integrin alphavbeta8; D011070:Poly I-C