The state diagram for cell adhesion mediated by two receptors
The state diagram for cell adhesion mediated by two receptors
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DOI：
10.1016/s0006-3495(03)75073-5
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发表时间：
2003-04-01
影响因子：
3.4
通讯作者：
Hammer, DA
中科院分区：
文献类型：
--
作者：
Bhatia, SK;King, MR;Hammer, DA
白细胞从血流募集到周围组织是免疫应答的重要组成部分。通过两步机制将血液传播的白细胞捕获到血管内皮上，每一步都由不同的受体-配体对介导。细胞首先短暂粘附或“滚动”（通过选择素和唾液酸-路易斯-x之间的相互作用），然后牢固粘附到血管壁（通过整合素和ICAM-1之间的相互作用）。我们已经报道了一种称为粘附动力学（AD）的计算方法准确地再现了选择素介导的滚动的精细尺度动力学。本文扩展了AD模拟的使用，以模拟两类受体同时激活时的细胞粘附动力学：一类（选择素或选择素配体）具有弱粘附特性，另一类（整合素）具有强粘附特性。AD模拟预测两种受体在介导粘附中的协同功能。在固定密度的表面ICAMI-1，增加选择素密度导致更大的停顿时间和增加的趋势，坚定的粘附，因此，选择素机械促进坚定的粘附介导的整联蛋白。相反，在固定密度的表面选择素，增加ICAM-1密度导致更大的停顿时间和增加的趋势，以坚定的粘附。我们在两个受体状态图中呈现这种关系，该图将粘附分子的密度和性质与它们编码的各种粘附行为（如滚动或牢固粘附）联系起来。我们还提出了一个中性粒细胞活化的状态图，它将β 2-整合素密度和整合素-ICAM-1动力学速率与中性粒细胞粘附行为联系起来。两个受体粘附动力学的预测进行验证的能力，该模型重现在体内中性粒细胞滚动速度从文献。
Leukocyte recruitment from the bloodstream to surrounding tissues is an essential component of the immune response. Capture of blood-borne leukocytes onto vascular endothelium proceeds via a two-step mechanism, with each step mediated by a distinct receptor-ligand pair. Cells first transiently adhere, or "roll" (via interactions between selectins and sialyl-Lewis-x), and then firmly adhere to the vascular wall (via interactions between integrins and ICAM-1). We have reported that a computational method called adhesive dynamics (AD) accurately reproduces the fine-scale dynamics of selectin-mediated rolling. This paper extends the use of AD simulations to model the dynamics of cell adhesion when two classes of receptors are simultaneously active: one class (selectins or selectin ligands) with weakly adhesive properties, and the other (integrins) with strongly adhesive properties. AD simulations predict synergistic functions of the two receptors in mediating adhesion. At a fixed density of surface ICAMI-1, increasing selectin densities lead to greater pause times and an increased tendency toward firm adhesion; thus, selectins mechanistically facilitate firm adhesion mediated by integrins. Conversely, at a fixed density of surface selectin, increasing ICAM-1 densities lead to greater pause times and an increased tendency to firm adhesion. We present this relationship in a two-receptor state diagram, a map that relates the densities and properties of adhesion molecules to various adhesive behaviors that they code, such as rolling or firm adhesion. We also present a state diagram for neutrophil activation, which relates beta(2)-integrin density and integrin-ICAM-1 kinetic on rate to neutrophil adhesive behavior. The predictions of two-receptor adhesive dynamics are validated by the ability of the model to reproduce in vivo neutrophil rolling velocities from the literature.