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Originally published online as doi:10.1189/jlb.0307133 on July 5, 2007

Published online before print July 5, 2007
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(Journal of Leukocyte Biology. 2007;82:946-955.)
© 2007 by Society for Leukocyte Biology

Expression and role of CCR6/CCL20 chemokine axis in pulmonary sarcoidosis

Monica Facco*,{dagger}, Ilenia Baesso*,{dagger}, Marta Miorin*, Michela Bortoli*, Anna Cabrelle{dagger}, Elisa Boscaro*, Carmela Gurrieri*,{dagger}, Livio Trentin*,{dagger}, Renato Zambello*,{dagger}, Fiorella Calabrese{ddagger}, Marco Antonio Cassatella§, Gianpietro Semenzato*,{dagger} and Carlo Agostini*,{dagger},1

* Department of Clinical and Experimental Medicine, Hematology-Immunology Division,
{dagger} Venetian Institute of Molecular Medicine, and
{ddagger} Department of Pathology, Padua University School of Medicine, Padova, Italy; and
§ Department of Pathology, Section of General Pathology, University of Verona, Verona, Italy

1 Correspondence: Padua University School of Medicine, Department of Clinical and Experimental Medicine, Hematology-Immunology Division, Via Giustiniani 2, 35128 Padova, Italy. E-mail: carlo.agostini{at}unipd.it

We have shown previously that the chemokine receptors CXCR3 and CXCR6 are coexpressed by Th1 cells infiltrating the lung and the granuloma of patients with sarcoidosis. In this study, we evaluated the role of CCL20/CCR6 interaction in the pathogenesis of acute and chronic pulmonary sarcoidosis. By flow cytometry and molecular analyses, we have demonstrated that Th1 cells isolated from the bronchoalveolar lavage (BAL) of patients with sarcoidosis and T cell alveolitis are equipped with CCR6. Furthermore, CCR6+ T cells coexpressed the chemokine receptors CXCR3 and CXCR6. Immunohistochemical analysis of lung specimens has shown that CCR6+ T cells infiltrate lung interstitium and surround the central core of the granuloma. It is interesting that CCR6 was never detected on the alveolar macrophage (AM) surface, and it is observed in the cytoplasm of AMs from patients with sarcoidosis and alveolitis. The CCR6 ligand CCL20 was expressed by macrophages, multinucleated giant cells, and epithelioid cells infiltrating the granuloma. Furthermore, detectable levels of CCL20 protein are seen in the BAL fluid components of patients with active sarcoidosis, and sarcoid AMs release the CCR6 ligand in vitro. From a functional point of view, sarcoid Th1 cells were able to respond to CXCL10, CXCL16, and CCL20 in migratory assays. In vitro kinetic studies demonstrated that CCR6 is induced rapidly by IL-2, IL-18, and IFN-{gamma}. In conclusion, T cells expressing CCR6, CXCR3, and CXCR6 act coordinately with respective ligands and Th1 inflammatory cytokines in the alveolitic/granuloma phases of the disease.

Key Words: T cells • macrophages • inflammation • lung