Expression and role of CCR6/CCL20 chemokine axis in pulmonary sarcoidosis
Expression and role of CCR6/CCL20 chemokine axis in pulmonary sarcoidosis
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DOI：
10.1189/jlb.0307133
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发表时间：
2007-10-01
影响因子：
5.5
通讯作者：
Agostini, Carlo
中科院分区：
文献类型：
--
作者：
Facco, Monica;Baesso, Ilenia;Agostini, Carlo
我们以前已经表明，趋化因子受体CXCR 3和CXCR 6共表达的Th 1细胞浸润肺和结节病患者的肉芽肿。在这项研究中，我们评估了CCL 20/CCR 6相互作用在急性和慢性肺结节病发病机制中的作用。通过流式细胞术和分子分析，我们已经证明，从结节病和T细胞肺泡炎患者的支气管肺泡灌洗液（BAL）中分离的Th 1细胞配备了CCR 6。此外，CCR 6（+）T细胞共表达趋化因子受体CXCR 3和CXCR 6。肺标本的免疫组织化学分析显示，CCR 6（+）T细胞浸润肺间质并包围肉芽肿的中心核心。有趣的是，CCR 6从未在肺泡巨噬细胞（AM）表面上检测到，并且在来自结节病和肺泡炎患者的AM的细胞质中观察到。CCR 6配体CCL 20由巨噬细胞、多核巨细胞和浸润肉芽肿的上皮样细胞表达。此外，在活动性结节病患者的BAL液成分中观察到可检测水平的CCL 20蛋白，并且结节样AM在体外释放CCR 6配体。从功能的角度来看，类肉瘤Th 1细胞能够响应CXCL 10，CXCL 16，和CCL 20在迁移试验。体外动力学研究表明，CCR 6被IL-2、IL-18和IFN-γ快速诱导。总之，表达CCR 6、CXCR 3和CXCR 6的T细胞在疾病的肺泡/肉芽肿阶段与各自的配体和Th 1炎性细胞因子协同作用。
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.