Chernokine sequestration by atypical chemokine receptors
Chernokine sequestration by atypical chemokine receptors
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DOI：
10.1042/bst0341009
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发表时间：
2006-12-01
影响因子：
3.9
通讯作者：
Nibbs, R. J. B.
中科院分区：
文献类型：
--
作者：
Hansell, C. A. H.;Simpson, C. V.;Nibbs, R. J. B.
白细胞迁移对于强大的免疫和炎症反应至关重要，并且在许多人类疾病中起着关键作用。趋化因子是一类小分子分泌型蛋白质趋化吸引物，在此过程中具有根本重要性，它通过迁移细胞所表达的七螺旋G蛋白偶联受体发出信号来引导白细胞的运输。然而，几种哺乳动物趋化因子受体，包括D6和CCX - CKR（ChemoCentryx趋化因子受体），并不符合现有的趋化因子受体功能模型，甚至在趋化因子结合时似乎也不发出信号。相反，这些“非典型”趋化因子受体在生物化学上专门用于趋化因子的隔离，起到调节趋化因子生物利用度的作用，从而通过有信号传导能力的趋化因子受体影响反应。这在体内至关重要，因为缺乏D6的小鼠表现出过度的皮肤炎症反应以及对皮肤癌发展的易感性增加。另一方面，预计CCX - CKR可调节稳态淋巴细胞和树突状细胞的运输，这是由M - M结合趋化因子引导的获得性免疫反应中的关键迁移事件。因此，对“非典型”趋化因子受体的研究揭示了趋化因子受体家族内的功能和生物化学多样性，并为趋化因子调节的新机制提供了见解。
Leucocyte migration is essential for robust immune and inflammatory responses, and plays a critical role in many human diseases. Chemokines, a family of small secreted protein chemoattractants, are of fundamental importance in this process, directing leucocyte trafficking by signalling through heptahelical G-protein-coupled receptors expressed by the migrating cells. However, several mammalian chemokine receptors, including D6 and CCX-CKR (ChemoCentryx chemokine receptor), do not fit existing models of chemokine receptor function, and do not even appear to signal in response to chemokine binding. Instead, these 'atypical' chemokine receptors are biochemically specialized for chemokine sequestration, acting to regulate chemokine bioavailability and thereby influence responses through signalling-competent chemokine receptors. This is of critical importance in vivo, as mice lacking D6 show exaggerated cutaneous inflammatory responses and an increased susceptibility to the development of skin cancer. CCX-CKR, on the other hand, is predicted to modulate homoeostatic lymphocyte and dendritic cell trafficking, key migratory events in acquired immune responses that are directed by M-M-binding chemokines. Thus studies on 'atypical' chemokine receptors are revealing functional and biochemical diversity within the chemokine receptor family and providing insights into novel mechanisms of chemokine regulation.