Expression and role of CCR6/CCL20 chemokine axis in pulmonary sarcoidosis.
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.
Facco
Monica
M
Department of Clinical and Experimental Medicine, Hematology-Immunology Division, Padua University School of Medicine, Via Giustiniani 2, 35128 Padova, Italy.
Baesso
Ilenia
I
Miorin
Marta
M
Bortoli
Michela
M
Cabrelle
Anna
A
Boscaro
Elisa
E
Gurrieri
Carmela
C
Trentin
Livio
L
Zambello
Renato
R
Calabrese
Fiorella
F
Cassatella
Marco Antonio
MA
Semenzato
Gianpietro
G
Agostini
Carlo
C
D000208:Acute Disease; D000328:Adult; D018893:Bronchoalveolar Lavage; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000096:biosynthesis / Q000276:immunology*; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000276:immunology; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000276:immunology; D002908:Chronic Disease; D015622:Epithelioid Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D015726:Giant Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015769:Granuloma, Respiratory Tract / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D020382:Interleukin-18 / Q000276:immunology / Q000494:pharmacology; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D054399:Receptors, CCR6 / Q000096:biosynthesis / Q000276:immunology*; D054367:Receptors, CXCR3; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000276:immunology; D051116:Receptors, Scavenger / Q000096:biosynthesis / Q000276:immunology; D011991:Receptors, Virus / Q000096:biosynthesis / Q000276:immunology; D017565:Sarcoidosis, Pulmonary / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
C108355:CCL20 protein, human; C106311:CCR6 protein, human; C114753:CXCL10 protein, human; C423727:CXCL16 protein, human; C515187:CXCR3 protein, human; C106330:CXCR6 protein, human; D054418:Chemokine CCL20; D054357:Chemokine CXCL10; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC; C508594:IL2 protein, human; D020382:Interleukin-18; D007376:Interleukin-2; D019402:Macrophage Inflammatory Proteins; D054399:Receptors, CCR6; D054367:Receptors, CXCR3; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D051116:Receptors, Scavenger; D011991:Receptors, Virus; D007371:Interferon-gamma