title: Cigarette smoke-induced pulmonary inflammation and emphysema are attenuated in CCR6-deficient mice.
abstract: Chronic obstructive pulmonary disease (COPD) is mainly caused by cigarette smoking, and is characterized by an increase in inflammatory cells in the airways and pulmonary tissue. The chemokine receptor CCR6 and its ligand MIP-3alpha/CCL20 may be involved in the recruitment of these inflammatory cells. To investigate the role of CCR6 in the pathogenesis of COPD, we analyzed the inflammatory responses of CCR6 knockout (KO) and wild-type mice upon cigarette smoke (CS) exposure. Both subacute and chronic exposure to CS induced an increase in cells of the innate and adaptive immune system in the bronchoalveolar lavage, both in CCR6 KO and wild-type mice. However, the accumulation of dendritic cells, neutrophils, and T lymphocytes, which express CCR6, was significantly attenuated in the CCR6 KO mice, compared with their wild-type littermates. In the lung tissue of CCR6 KO mice, there was an impaired increase in dendritic cells, activated CD8(+) T lymphocytes, and granulocytes. Moreover, this attenuated inflammatory response in CCR6 KO mice offered a partial protection against pulmonary emphysema, which correlated with an impaired production of MMP-12. Importantly, protein levels of MIP-3alpha/CCL20, the only chemokine ligand of the CCR6 receptor, and MCP-1/CCL2 were significantly increased upon CS exposure in wild-type, but not in CCR6 KO mice. In contrast, CCR6 deficiency had no effect on the development of airway wall remodeling upon chronic CS exposure. These results indicate that the interaction of CCR6 with its ligand MIP-3alpha contributes to the pathogenesis of CS-induced pulmonary inflammation and emphysema in this murine model of COPD.
authors.affiliation: Department of Respiratory Diseases, Ghent University Hospital 7K12ie, De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Ken R
authors.initials: KR
authors.lastname: Bracke
authors.forename: An I
authors.initials: AI
authors.lastname: D'hulst
authors.forename: Tania
authors.initials: T
authors.lastname: Maes
authors.forename: Katrien B
authors.initials: KB
authors.lastname: Moerloose
authors.forename: Ingel K
authors.initials: IK
authors.lastname: Demedts
authors.forename: Serge
authors.initials: S
authors.lastname: Lebecque
authors.forename: Guy F
authors.initials: GF
authors.lastname: Joos
authors.forename: Guy G
authors.initials: GG
authors.lastname: Brusselle
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D054418:Chemokine CCL20; D019742:Chemokines, CC / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006098:Granulocytes / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000276:immunology / Q000378:metabolism; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011014:Pneumonia / Q000209:etiology / Q000276:immunology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000276:immunology / Q000473:pathology; D011656:Pulmonary Emphysema / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D054399:Receptors, CCR6; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking / Q000009:adverse effects; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: C108355:CCL20 protein, human; C498126:CCR6 protein, mouse; D054418:Chemokine CCL20; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D054399:Receptors, CCR6; D019707:Receptors, Chemokine; D014028:Tobacco Smoke Pollution; D008666:Metalloendopeptidases; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12