Leukocyte phosphoinositide-3 kinase γ is required for chemokine-induced, sustained adhesion under flow in vivo
Leukocyte phosphoinositide-3 kinase γ is required for chemokine-induced, sustained adhesion under flow in vivo
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DOI：
10.1189/jlb.0306227
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发表时间：
2006-12-01
影响因子：
5.5
通讯作者：
Ley, Klaus
中科院分区：
文献类型：
--
作者：
Smith, David F.;Deem, Tracy L.;Ley, Klaus
炎症期间，白细胞沿着毛细血管后小静脉壁滚动，扫描表面寻找固定的CXCL1， CXCL1是一种通过激活中性粒细胞上的CXCR2触发牢固粘附的趋化因子。PI-3K是在细胞分化到白细胞迁移等细胞过程中重要的信号分子。PI-3K γ可以被异源三聚体G蛋白的β - γ二聚体与CXCR2偶联直接激活。在这里，我们使用体内和离体活体显微镜模型来测试PI-3K γ在白细胞阻滞中的作用。PI-3K γ缺失小鼠显示cxcl1诱导的小鼠外肌小静脉中白细胞粘附减少80%。在野生型小鼠中，滚动白细胞表现出快速和持续的粘附，但在PI-3K γ(-/-)小鼠中，粘附根本没有被触发或只是短暂的，这表明PI-3K γ的缺失干扰了整合素结合的加强。用PI-3K γ缺失骨髓重建的野生型小鼠显示cxcl1诱导的白细胞粘附减少50%。在血液灌注的微流室中，来自PI-3K-y-/-小鼠的白细胞在p -选择素/ICAM-1/CXCL1底物上的粘附缺陷，表明粘附需要白细胞PI-3K- γ。PI-3K γ(-/-)小鼠的粘附缺陷与缺乏LFA-1的小鼠一样严重，LFA-1是负责中性粒细胞粘附的主要整合素。我们得出结论，PI-3K的γ亚型必须在白细胞中发挥功能，以使其在趋化因子刺激下有效粘附。
During inflammation, leukocytes roll along the wall of postcapillary venules scanning the surface for immobilized CXCL1, a chemokine that triggers firm adhesion by activating CXCR2 on the neutrophil. PI-3K are signaling molecules important in cellular processes, ranging from cellular differentiation to leukocyte migration. PI-3K gamma can be activated directly by the beta gamma dimer of heterotrimeric G proteins coupled to CXCR2. Here, we used in vivo and ex vivo intravital microscopy models to test the role of PI-3K gamma in leukocyte arrest. PI-3K gamma null mice showed an 80% decrease in CXCL1-induced leukocyte adhesion in venules of the exteriorized mouse cremaster muscle. In wildtype mice, rolling leukocytes showed rapid and sustained adhesion, but in PI-3K gamma(-/-) mice, adhesion was not triggered at all or was transient, suggesting that absence of PI-3K gamma interferes with integrin bond strengthening. Wild-type mice reconstituted with PI-3K gamma null bone marrow showed a 50% decrease in CXCL1-induced leukocyte adhesion. In a blood-perfused micro-flow chamber, leu-kocytes from PI-3K-y-/- mice showed a defect in adhesion on a P-selectin/ICAM-1/CXCL1 substrate, indicating that leukocyte PI-3K gamma was required for adhesion. The adhesion defect in PI-3K gamma(-/-) mice was as severe as that in mice lacking LFA-1, the major integrin responsible for neutrophil adhesion. We conclude that the gamma isoform of PI-3K must be functional in leukocytes to allow efficient adhesion from rolling in response to chemokine stimulation.