Krasik Ellen F, Caputo Kelly E, Hammer Daniel A
Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Biophys J. 2008 Aug;95(4):1716-28. doi: 10.1529/biophysj.107.119677. Epub 2008 May 16.
The transition from rolling to firm adhesion is a key step in the adhesion cascade that permits a neutrophil to exit the bloodstream and make its way to a site of inflammation. In this work, we construct an integrated model of neutrophil activation and arrest that combines a biomechanical model of neutrophil adhesion and adhesive dynamics, with fully stochastic signal transduction modeling, in the form of kinetic Monte Carlo simulation within the microvilli. We employ molecular binding parameters gleaned from the literature and from simulation of cell-free rolling mediated by selectin molecules. We create a simplified model of lymphocyte function-associated antigen-1 activation that links P-selectin glycoprotein ligand-1 ligation to integrin activation. The model utilizes an energy profile of various integrin activation states drawn from literature data and permits manipulation of signal diffusivity within the microvillus. Our integrated model recreates neutrophil arrest within physiological timescales, and we demonstrate that increasing signal diffusivity within a microvillus accelerates arrest. If the energy barrier between free unactivated and free activated lymphocyte function-associated antigen-1 increases, the period of rolling before arrest increases. We further demonstrate that, within our model, modification of endothelial ligand surface densities can control arrest. In addition, the relative concentrations of signaling molecules control the fractional activation of the overall signaling pathway and the rolling time to arrest. This work presents the first, to our knowledge, fully stochastic model of neutrophil activation, which, though simplified, can recapitulate significant physiological details of neutrophil arrest yet retains the capacity to incorporate additional information regarding mechanisms of neutrophil signal transduction as they are elucidated.
从滚动到牢固黏附的转变是黏附级联反应中的关键步骤，它使中性粒细胞能够离开血流并前往炎症部位。在这项工作中，我们构建了一个中性粒细胞激活和停滞的综合模型，该模型将中性粒细胞黏附及黏附动力学的生物力学模型与完全随机的信号转导模型相结合，采用微绒毛内动力学蒙特卡罗模拟的形式。我们采用从文献以及选择素分子介导的无细胞滚动模拟中收集的分子结合参数。我们创建了一个淋巴细胞功能相关抗原-1激活的简化模型，该模型将P-选择素糖蛋白配体-1的连接与整合素激活联系起来。该模型利用从文献数据中得出的各种整合素激活状态的能量分布，并允许对微绒毛内的信号扩散率进行操控。我们的综合模型在生理时间尺度内重现了中性粒细胞的停滞，并且我们证明增加微绒毛内的信号扩散率会加速停滞。如果游离未激活和游离激活的淋巴细胞功能相关抗原-1之间的能量屏障增加，停滞前的滚动期会增加。我们进一步证明，在我们的模型中，内皮配体表面密度的改变可以控制停滞。此外，信号分子的相对浓度控制着整个信号通路的部分激活以及滚动至停滞的时间。据我们所知，这项工作提出了首个中性粒细胞激活的完全随机模型，该模型虽然简化，但能够概括中性粒细胞停滞的重要生理细节，并且在阐明中性粒细胞信号转导机制时仍保留纳入其他信息的能力。
