The CXCR1/2 ligand NAP-2 promotes directed intravascular leukocyte migration through platelet thrombi
The CXCR1/2 ligand NAP-2 promotes directed intravascular leukocyte migration through platelet thrombi
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DOI：
10.1182/blood-2012-09-459636
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发表时间：
2013-05-30
期刊：
影响因子：
20.3
通讯作者：
Jackson, Shaun P.
中科院分区：
文献类型：
--
作者：
Ghasemzadeh, Mehran;Kaplan, Zane S.;Jackson, Shaun P.
血栓形成促进白细胞浸润到炎症组织中，导致广泛疾病中的器官损伤;然而，血栓引导白细胞到达血管损伤部位的机制仍然不清楚。使用内皮损伤（创伤或缺血再灌注）的小鼠模型，我们证明了一个独特的白细胞募集过程，称为“定向血管内迁移”，专门介导的血小板血栓。单个粘附血小板和血小板聚集体刺激内皮损伤部位的白细胞形状改变;然而，只有血栓能够诱导定向血管内白细胞迁移。血小板血栓引起的白细胞募集和迁移主要发生在静脉，但也可发生在缺血再灌注损伤后的动脉。体外研究表明，血小板衍生的NAP-2（CXCL-7）及其CXCR 1/2受体在调节白细胞极化和运动中发挥重要作用。体内研究表明血栓体内存在NAP-2趋化梯度。CXCR 1/2的药物阻断以及NAP-2的基因缺失显著减少了白细胞形状改变和血栓内迁移。这些研究定义了一个独特的白细胞迁移过程，该过程由血小板之间的同型粘附相互作用引发，导致血栓体内NAP-2趋化梯度的形成，将白细胞引导至血管损伤部位。
Thrombosis promotes leukocyte infiltration into inflamed tissues, leading to organ injury in a broad range of diseases; however, the mechanisms by which thrombi guide leukocytes to sites of vascular injury remain ill-defined. Using mouse models of endothelial injury (traumatic or ischemia reperfusion), we demonstrate a distinct process of leukocyte recruitment, termed "directed intravascular migration," specifically mediated by platelet thrombi. Single adherent platelets and platelet aggregates stimulated leukocyte shape change at sites of endothelial injury; however, only thrombi were capable of inducing directed intravascular leukocyte migration. Leukocyte recruitment and migration induced by platelet thrombi occurred most prominently in veins but could also occur in arteries following ischemia-reperfusion injury. In vitro studies demonstrated a major role for platelet-derived NAP-2 (CXCL-7) and its CXCR1/2 receptor in regulating leukocyte polarization and motility. In vivo studies demonstrated the presence of an NAP-2 chemotactic gradient within the thrombus body. Pharmacologic blockade of CXCR1/2 as well as genetic deletion of NAP-2 markedly reduced leukocyte shape change and intrathrombus migration. These studies define a distinct process of leukocyte migration that is initiated by homotypic adhesive interactions between platelets, leading to the development of an NAP-2 chemotactic gradient within the thrombus body that guides leukocytes to sites of vascular injury.