Lipid raft adhesion receptors and Syk regulate selectin-dependent rolling under flow conditions
Lipid raft adhesion receptors and Syk regulate selectin-dependent rolling under flow conditions
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DOI：
10.1182/blood-2006-04-013912
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发表时间：
2006-11-15
期刊：
影响因子：
20.3
通讯作者：
Spertini, Olivier
中科院分区：
文献类型：
--
作者：
Abbal, Claire;Lambelet, Martine;Spertini, Olivier
选择素及其配体P-选择素糖蛋白配体-1（PSGL-1）介导白细胞沿着炎症血管滚动。细胞滚动是由选择素与其配体的相互作用和地形的要求，包括L-选择素和PSGL-1聚集在白细胞微绒毛的尖端调制。脂筏是细胞膜上的一种微结构域，具有信号传导平台的功能。在这里，我们表明，破坏白细胞脂筏与胆固醇螯合剂耗尽筏相关的PSGL-1和L-选择素，并强烈降低L-，P-和E-选择素依赖的滚动。胆固醇补充逆转了细胞滚动的抑制。重要的是，白细胞在P-选择素上滚动诱导脾酪氨酸激酶（Syk）的募集，这是一种与脂筏PSGL-1相关的酪氨酸激酶。此外，用药理学抑制剂或通过RNA干扰抑制Syk活性或表达，强烈降低了白细胞在P-选择素上的滚动，但对E-选择素或PSGL-1没有。这些观察结果确定了新的调节机制，白细胞滚动的选择素与脂筏完整性和Syk活性的强烈依赖。
Selectins and their ligand P-selectin glycoprotein ligand-1 (PSGL-1) mediate leukocyte rolling along inflamed vessels. Cell rolling is modulated by selectin interactions with their ligands and by topographic requirements including L-selectin and PSGL-1 clustering on tips of leukocyte microvilli. Lipid rafts are cell membrane microdomains reported to function as signaling platforms. Here, we show that disruption of leukocyte lipid rafts with cholesterol chelating agents depleted raft-associated PSGL-1 and L-selectin and strongly reduced L-, P-, and E-selectin-dependent rolling. Cholesterol repletion reversed inhibition of cell rolling. Importantly, leukocyte rolling on P-selectin induced the recruitment of spleen tyrosine kinase (Syk), a tyrosine kinase associated to lipid raft PSGL-1. Furthermore, inhibition of Syk activity or expression, with pharmacologic inhibitors or by RNA interference, strongly reduced leukocyte rolling on P-selectin, but not on E-selectin or PSGL-1. These observations identify novel regulatory mechanisms of leukocyte rolling on selectins with a strong dependency on lipid raft integrity and Syk activity.