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Mechanisms regulating leukocyte rolling mediated by selectin ligand PSGL-1

选择素配体 PSGL-1 介导的白细胞滚动调节机制

基本信息

批准号：
15590438
负责人：
HIRATA Takako
金额：
$ 2.3万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590438/
关键词：
leukocyte rolling adhesion molecules selectins integrins PSGL-1 LFA-1 ICAM-1 Th1 cells

项目摘要

Leukocytes migrate from the blood into non-lymphoid tissues through a multi-step process that involves cell rolling, arrest, and transmigration. Although the role of P-selectin glycoprotein ligand-1 (PSGL-1), a major ligand for P-selectin expressed on leukocytes, as a rolling receptor has been clarified, the mechanisms regulating the PSGL-1-mediated rolling and the transition from rolling to arrest are not well understood. In this research project, we clarified two PSGL-1-mediated mechanisms that can regulate the transition form rolling to arrest. The first mechanism is the PSGL-1-mediated stimulation of LFA-1-dependent cell adhesion. We showed that antibody-mediated cross-linking of the PSGL-1 on Th1 cells enhances LFA-1-dependent cell binding to ICAM-1. Combined stimulation by PSGL-1 cross-linking and the Th1-stimulating chemokine CXCL10 (IP-10) or CCLS (RANTES) showed a more-than additive effect on LFA-1-mediated Th1 cell adhesion as well as on LFA-1 redistribution on the cell surface. Moreover, PSGL-1-mediated rolling on P-selectin enhanced the Th1 cell accumulation on ICAM-1 under flow conditions. These results support the idea that PSGL-1-mediated rolling interactions induce intracellular signals leading to integrin activation, facilitating Th1-cell arrest and subsequent migration into target tissues. The second mechanism is the interaction of PSGL-1 with chemokines. We showed that human PSGL-1 interacts with CCL27 (CTACK), and that sulfated tyrosines play a critical role in the CCL27-PSGL-1 interaction. Functionally, PSGL-1 reduced the chemotaxis of L1.2 cells expressing CCR10, the receptor for CCL27. Regulation of chemokine-mediated responses by PSGL-1 may affect the transition from rolling to chemokine-mediated arrest during leukocyte migration.

白细胞通过涉及细胞滚动、停滞和迁移的多步骤过程从血液迁移到非淋巴组织。尽管P-选择素糖蛋白配体-1 (PSGL-1)（白细胞上表达的P-选择素的主要配体）作为滚动受体的作用已被阐明，但调节PSGL-1介导的滚动和从滚动到停滞的转变的机制尚不清楚。在这个研究项目中，我们阐明了两种 PSGL-1 介导的机制，可以调节从滚动到停止的转变。第一个机制是 PSGL-1 介导的 LFA-1 依赖性细胞粘附刺激。我们发现，抗体介导的 Th1 细胞上 PSGL-1 的交联增强了 LFA-1 依赖性细胞与 ICAM-1 的结合。 PSGL-1 交联和 Th1 刺激趋化因子 CXCL10 (IP-10) 或 CCLS (RANTES) 的联合刺激显示出对 LFA-1 介导的 Th1 细胞粘附以及细胞表面上 LFA-1 重新分布的超加性效应。此外，在流动条件下，PSGL-1 介导的 P-选择素滚动增强了 Th1 细胞在 ICAM-1 上的积累。这些结果支持这样的观点，即 PSGL-1 介导的滚动相互作用诱导细胞内信号导致整合素激活，促进 Th1 细胞停滞并随后迁移到靶组织中。第二种机制是 PSGL-1 与趋化因子的相互作用。我们证明人类 PSGL-1 与 CCL27 (CTACK) 相互作用，并且硫酸化酪氨酸在 CCL27-PSGL-1 相互作用中发挥关键作用。从功能上讲，PSGL-1 降低了表达 CCR10（CCL27 受体）的 L1.2 细胞的趋化性。 PSGL-1 对趋化因子介导的反应的调节可能会影响白细胞迁移过程中从滚动到趋化因子介导的停滞的转变。