Biomedical Research Centre, Faculty of Health and Wellbeing, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, UK.
Brain Res. 2012 Feb 9;1437:115-26. doi: 10.1016/j.brainres.2011.11.049. Epub 2011 Dec 4.
Chemokines are low relative molecular mass proteins, which have chemoattractant actions on many cell types. The chemokine, CCL2, has been shown to play a major role in the recruitment of monocytes in central nervous system (CNS) lesions in multiple sclerosis (MS). Since resident astrocytes constitute a major source of chemokine synthesis including CCL2, we were interested to assess the regulation of CCL2 by astrocytes. We showed that CCL2 bound to the cell surface of astrocytes and binding was not modulated by inflammatory conditions. However, CCR2 protein was not detected nor was activation of the classical CCR2 downstream signaling pathways. Recent studies have shown that non-signaling decoy chemokine receptors bind and modulate the expression of chemokines at site of inflammation. Here, we show that the D6 chemokine decoy receptor is constitutively expressed by primary human adult astrocytes at both mRNA and protein level. In addition, CCL3, which binds to D6, but not CCL19, which does not bind to D6, displaced CCL2 binding to astrocytes; indicating that CCL2 may bind to this cell type via the D6 receptor. Our results suggest that CCL2 binding to primary adult human astrocytes is CCR2-independent and is likely to be mediated via the D6 decoy chemokine receptor. Therefore we propose that astrocytes are implicated in both the establishment of chemokine gradients for the migration of leukocytes into and within the CNS and in the regulation of CCL2 levels at inflammatory sites in the CNS.
趋化因子是低相对分子质量的蛋白质，对许多细胞类型具有趋化作用。趋化因子 CCL2 已被证明在多发性硬化症（MS）中枢神经系统（CNS）病变中单核细胞的募集中起主要作用。由于驻留星形胶质细胞构成趋化因子合成的主要来源，包括 CCL2，我们有兴趣评估星形胶质细胞对 CCL2 的调节。我们表明 CCL2 与星形胶质细胞的细胞表面结合，并且结合不受炎症条件的调节。然而，未检测到 CCR2 蛋白，也未激活经典的 CCR2 下游信号通路。最近的研究表明，非信号传导诱饵趋化因子受体结合并调节炎症部位趋化因子的表达。在这里，我们表明 D6 趋化因子诱饵受体在原代人成体星形胶质细胞中以 mRNA 和蛋白水平均持续表达。此外，与 D6 结合的 CCL3，而不与 D6 结合的 CCL19，取代 CCL2 与星形胶质细胞的结合；表明 CCL2 可能通过 D6 受体与这种细胞类型结合。我们的结果表明，CCL2 与原代成人星形胶质细胞的结合不依赖于 CCR2，并且可能通过 D6 诱饵趋化因子受体介导。因此，我们提出星形胶质细胞既参与白细胞向 CNS 内和内迁移的趋化因子梯度的建立，也参与 CNS 内炎症部位 CCL2 水平的调节。
