An engineered CX3CR1 antagonist endowed with anti-inflammatory activity
An engineered CX3CR1 antagonist endowed with anti-inflammatory activity
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DOI：
10.1189/jlb.0308158
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发表时间：
2009-10-01
影响因子：
5.5
通讯作者：
Deterre, Philippe
中科院分区：
文献类型：
--
作者：
Dorgham, Karim;Ghadiri, Ata;Deterre, Philippe
趋化因子主要参与白细胞向组织中的募集，这是炎症的一个关键特征。通过其独特的受体CX 3CR 1，趋化因子CX 3CL 1参与多种炎症过程，包括动脉粥样硬化和脑或肾炎症。使用噬菌体展示策略，我们设计了具有修饰的N末端的hCX 3CL 1类似物（命名为F1）。F1特异性结合表达hCX 3CR 1的细胞，并且具有接近天然CX 3CL 1的K-d值。F1不是信号分子，不诱导趋化性、钙流或CX 3CR 1内化。然而，它有效抑制CX 3CL 1诱导的钙通量和趋化性在CX 3CR 1表达的人和鼠源原代细胞中，IC 50为5-50 nM。它还有效地抑制由CX 3CL 1-CX 3CR 1轴介导的细胞粘附。最后，在非感染性小鼠腹膜炎模型中，F1强烈抑制巨噬细胞蓄积。这些数据揭示了一个原型分子，它是hCX 3CR 1的第一个真正的拮抗剂。这种分子可用作开发一类通过抑制CX 3CR 1起作用的新型抗炎物质的先导化合物。J. Leukoc. 86：903-911; 2009.
Chemokines are mainly involved in the recruitment of leukocytes into tissues, a key feature of inflammation. Through its unique receptor CX3CR1, the chemokine CX3CL1 participates in diverse inflammatory processes including arterial atherosclerosis and cerebral or renal inflammation. Using a phage display strategy, we engineered a hCX3CL1 analog (named F1) with a modified N terminus. F1 bound specifically to cells expressing hCX3CR1 and had a K-d value close to that of native CX3CL1. F1 was not a signaling molecule and did not induce chemotaxis, calcium flux, or CX3CR1 internalization. However, it potently inhibited the CX3CL1-induced calcium flux and chemotaxis in CX3CR1-expressing primary cells of human and murine origin with an IC50 of 5-50 nM. It also efficiently inhibited the cell adhesion mediated by the CX3CL1-CX3CR1 axis. Finally, in a noninfectious murine model of peritonitis, F1 strongly inhibited macrophage accumulation. These data reveal a prototype molecule that is the first bona fide antagonist of hCX3CR1. This molecule could be used as a lead compound for the development of a novel class of anti-inflammatory substances that act by inhibiting CX3CR1. J. Leukoc. Biol. 86: 903-911; 2009.