Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
Proc Natl Acad Sci U S A. 2012 Mar 20;109(12):4598-603. doi: 10.1073/pnas.1118104109. Epub 2012 Mar 5.
The recruitment of T lymphocytes during diseases such as rheumatoid arthritis is regulated by stimulation of the chemokine receptors expressed by these cells. This study was designed to assess the potential of a CXCR3-specific small-molecule agonist to inhibit the migration of activated human T cells toward multiple chemokines. Further experiments defined the molecular mechanism for this anti-inflammatory activity. Analysis in vitro demonstrated agonist induced internalization of both CXCR3 and other chemokine receptors coexpressed by CXCR3(+) T cells. Unlike chemokine receptor-specific antagonists, the CXCR3 agonist inhibited migration of activated T cells toward the chemokine mixture in synovial fluid from patients with active rheumatoid arthritis. A humanized mouse air-pouch model showed that intravenous treatment with the CXCR3 agonist prevented inflammatory migration of activated human T cells toward this synovial fluid. A potential mechanism for this action was defined by demonstration that the CXCR3 agonist induces receptor cross-phosphorylation within CXCR3-CCR5 heterodimers on the surface of activated T cells. This study shows that generalized chemokine receptor desensitization can be induced by specific stimulation of a single chemokine receptor on the surface of activated human T cells. A humanized mouse model was used to demonstrate that this receptor desensitization inhibits the inflammatory response that is normally produced by the chemokines present in synovial fluid from patients with active rheumatoid arthritis.
在类风湿关节炎等疾病中，T 淋巴细胞的募集受这些细胞表达的趋化因子受体的刺激调节。本研究旨在评估 CXCR3 特异性小分子激动剂抑制激活的人 T 细胞向多种趋化因子迁移的潜力。进一步的实验确定了这种抗炎活性的分子机制。体外分析表明激动剂诱导 CXCR3(+)T 细胞共表达的 CXCR3 和其他趋化因子受体内化。与趋化因子受体特异性拮抗剂不同，CXCR3 激动剂抑制了激活的 T 细胞向来自活动性类风湿关节炎患者滑液中趋化因子混合物的迁移。人源化小鼠气囊中模型表明，CXCR3 激动剂的静脉内治疗可防止激活的人 T 细胞向这种滑液中炎症性迁移。通过证明 CXCR3 激动剂诱导激活的 T 细胞表面的 CXCR3-CCR5 异二聚体中的受体交叉磷酸化，定义了这种作用的潜在机制。这项研究表明，通过对激活的人 T 细胞表面上的单个趋化因子受体的特异性刺激，可以诱导普遍的趋化因子受体脱敏。使用人源化小鼠模型证明，这种受体脱敏抑制了通常由来自活动性类风湿关节炎患者滑液中存在的趋化因子产生的炎症反应。
