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* Department of Respiratory Diseases, Ghent University Hospital, Ghent, Belgium; and
Service de Pneumologie, Centre Hospitalier Universitaire-Lyon, France
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-3
/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-3/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-3 contributes to the pathogenesis of CS-induced pulmonary inflammation and emphysema in this murine model of COPD.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Fund for Scientific Research in Flanders (Fonds Wetenschappelijk Onderzoek Vlaanderen, Research Project G.0011.03), the Strategic Basic Research (Strategisch Basisonderzoek-Instituut voor de Aanmoediging van Innovatie door Wetenschap en Technologie in Vlaanderen/020203), and the Concerted Research Action of the University of Ghent (BOF/GOA 01251504).
2 Address correspondence and reprint requests to Dr. Guy G. Brusselle, Department of Respiratory Diseases, Ghent University Hospital 7K12ie, De Pintelaan 185, 9000 Ghent, Belgium. E-mail address: guy.brusselle{at}UGent.be
3 Abbreviations used in this paper: COPD, chronic obstructive pulmonary disease; BAL, bronchoalveolar lavage; CBA, cytometric bead array; CS, cigarette smoke; DC, dendritic cell; DI, destructive index; hprt, hypoxanthine guanine phosphoribosyltransferase; KO, knockout; Lm, mean linear intercept; MMP, matrix metalloproteinase; Pbm, length of the basement membrane.
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