Krasik Ellen F, Yee Ka Lai, Hammer Daniel A
Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Biophys J. 2006 Aug 15;91(4):1145-55. doi: 10.1529/biophysj.105.070706. Epub 2006 May 26.
The transition from rolling to firm adhesion is a key element of neutrophil activation and essential to the inflammatory response. Although the molecular mediators of rolling and firm adhesion are known to be selectins and beta2 -integrins, respectively, the precise dynamic mechanism by which these ligands facilitate neutrophil arrest remains unknown. Recently, it has been shown that ligation of E-selectin can stimulate the firm adhesion of neutrophils via a MAP-kinase cascade. To study the possible mechanism by which neutrophil arrest could occur, we created an integrated model by combining two methodologies from computational biology: a mechanics-based modeling of leukocyte adhesion (adhesive dynamics) and signal transduction pathway modeling. Within adhesive dynamics, a computational method our group has shown to accurately recreate rolling dynamics, we include a generic, tunable integrin activation module that links selectin engagement to integrin and activity. This model allows us to relate properties of the activation function to the dynamics of rolling and the time and distance rolled before arrest. This integrated model allows us to understand how intracellular signaling activity can set the timescale of neutrophil activation, adhesion, and diapedesis.
从滚动到牢固黏附的转变是中性粒细胞激活的关键要素，对炎症反应至关重要。尽管已知滚动和牢固黏附的分子介质分别是选择素和β2整合素，但这些配体促进中性粒细胞停滞的确切动态机制仍不清楚。最近，研究表明E选择素的连接可通过丝裂原活化蛋白激酶级联反应刺激中性粒细胞的牢固黏附。为了研究中性粒细胞停滞可能发生的机制，我们通过结合计算生物学的两种方法创建了一个综合模型：基于力学的白细胞黏附建模（黏附动力学）和信号转导途径建模。在黏附动力学中，我们团队已证明该计算方法能准确重现滚动动力学，我们纳入了一个通用的、可调节的整合素激活模块，该模块将选择素结合与整合素及其活性联系起来。该模型使我们能够将激活函数的特性与滚动动力学以及停滞前滚动的时间和距离联系起来。这个综合模型使我们能够理解细胞内信号活动如何设定中性粒细胞激活、黏附和穿膜迁移的时间尺度。
