Right on the spot - Chemokine triggering of integrin-mediated arrest of rolling leukocytes
Right on the spot - Chemokine triggering of integrin-mediated arrest of rolling leukocytes
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DOI：
10.1160/th05-07-0482
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发表时间：
2006-01-01
影响因子：
6.7
通讯作者：
Alon, R
中科院分区：
文献类型：
--
作者：
Laudanna, C;Alon, R
在各种靶血管床上滚动的白细胞的停滞对于它们在炎症部位和次级淋巴组织的募集至关重要。白细胞停滞主要由整合素介导，整合素与组成型或诱导型内皮配体相互作用。整合素是细胞内调节的异源二聚体，在循环白细胞上维持在很低的亲和力构象状态。为了发生阻滞，当白细胞遇到适当的内皮展示趋化因子或化学引诱物时，整联蛋白异二聚体的亲和力必须原位增强，所述趋化因子或化学引诱物通过白细胞表面上的特异性G蛋白偶联受体（GPCR）结合并发出信号。最近的研究表明，这种整合素的激活涉及快速的构象变化，局部诱导在有限的白细胞内皮细胞接触网站。结合后，整合素微簇与皮质肌动蛋白细胞骨架协会加强进一步增强整合素介导的剪切应力下的粘附。这些事件由复杂的信号传导事件控制，涉及一系列小GTP酶，以及由趋化因子结合的GPCR触发的蛋白质和脂质激酶。为了快速介导这种专门的功能，信号蛋白及其特异性靶标的子集被认为预先存在于预组装的多分子复合物或信号体中。最近在体外解剖趋化因子触发的整合素激活淋巴细胞和中性粒细胞表明，这些信号体可能会有所不同，在不同的免疫细胞类型和不同的整合素之间的组成和活动模式。在这篇文章中，我们回顾了最近的研究结果，涉及在趋化因子触发整合素激活滚动白细胞的关键要素，并讨论了可能存在的预制proadhesion信号网络在不同的白细胞亚群。
The arrest of rolling leukocytes on various target vascular beds is crucial for their recruitment at inflammatory sites and secondary lymphoid tissues. Leukocyte arrest is predominantly mediated by integrins interacting with either constitutive or inducible endothelial ligands. Integrins are cytoskeletally regulated heterodimers maintained in largely low affinity conformational states on circulating leukocytes. For arrest to occur, the affinity of integrin heterodimers must be enhanced in situ upon leukocyte encounter with proper endothelial-displayed chemokines or chemoattractants which bind and signal through specific G-protein coupled receptors (GPCRs) on the leukocyte surface. Recent studies suggest that this integrin activation involves rapid conformational alterations locally induced at confined leukocyte-endothelial contact sites. Following binding, integrin microclustering reinforced by associations with the cortical actin cytoskeleton further enhances integrin-mediated adhesiveness under shear stress. These events are controlled by complex signaling events, involving a series of small GTPases, as well as protein and lipid kinases which are triggered by chemokine bound GPCRs. To rapidly mediate this specialized function, subsets of signaling proteins and their specific targets are thought to preexist in pre-assembled multi-molecular complexes or signalosomes. Recent in vitro dissection of chemokine-triggered integrin activation on lymphocytes and neutrophils suggests that these signalosomes may vary both in composition and mode of activity between different immune cell types and distinct integrins. We review in this article recent findings on key elements implicated in chemokine triggering of integrin activation on rolling leukocytes, and discuss the possible existence of preformed proadhesive signaling networks in different subsets of leukocytes.