A mathematical model for neutrophil gradient sensing and polarization.
A mathematical model for neutrophil gradient sensing and polarization.
复制标题
中性粒细胞梯度传感和极化的数学模型。
DOI：
10.1371/journal.pcbi.0030036
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发表时间：
2007-03-16
影响因子：
4.3
通讯作者：
Rao CV
中科院分区：
文献类型：
--
作者：
Onsum M;Rao CV
细胞响应化学信号的定向迁移，也被称为趋化性，是一个重要的生理过程，涉及伤口愈合、觅食和免疫反应。细胞迁移需要在细胞边缘同时形成肌动蛋白聚合物，在细胞两侧和后部同时形成肌动球蛋白复合物。真核生物趋化性的一个未解决的问题是相同的趋化信号如何决定细胞的正面和背面。最近的实验研究已经开始揭示这种极化细胞反应所必需的生化机制。基于实验表征的生化机制，我们提出了中性粒细胞梯度传感和极化的数学模型。该模型表明，已知的Rho GTPase和磷脂酰肌醇-3激酶（PI3K）激活动力学足以实现梯度传感和极化。特别是，该模型表明，这些机制可以正确定位“前”和“后”通路，以响应均匀浓度和梯度的化学引诱剂，包括在肌动蛋白抑制细胞中。此外，模型预测对许多参数值具有鲁棒性。该模型的一个关键结果是提出了涉及PI3K和Ras的重合回路，消除了对“全局抑制剂”的需求，尽管在许多以前的真核趋化性数学模型中从未得到实验验证。最后，我们提出了实验来验证这个模型，并进一步了解中性粒细胞趋化性。中性粒细胞通过感知受损组织和感染微生物产生的化学信号，以感染和炎症部位为目标，然后向它们浓度最高的方向移动。一个悬而未决的问题是中性粒细胞如何整合这些信息来确定运动的方向。我们提出了调节中性粒细胞极化和趋化的细胞内信号网络的数学模型。我们展示了两种拮抗途径的激活如何牢固地建立了迁移细胞的前部和后部。该模型能够再现许多实验研究，并且提出了新的实验来测试该模型的不同方面。一个关键的结果是表征了一个涉及磷脂酰肌醇-3激酶（PI3K）和Ras的重合回路。我们证明，该回路在选择性地将f -肌动蛋白定位到细胞前部和将肌动球蛋白复合物定位到细胞后部方面起着关键作用。由于响应化学信号的定向运动在包括伤口愈合和肿瘤转移在内的许多过程中都是至关重要的，因此从该模型中获得的结果和见解可能适用于其他细胞类型和生物体。
Directed cell migration in response to chemical cues, also known as chemotaxis, is an important physiological process involved in wound healing, foraging, and the immune response. Cell migration requires the simultaneous formation of actin polymers at the leading edge and actomyosin complexes at the sides and back of the cell. An unresolved question in eukaryotic chemotaxis is how the same chemoattractant signal determines both the cell's front and back. Recent experimental studies have begun to reveal the biochemical mechanisms necessary for this polarized cellular response. We propose a mathematical model of neutrophil gradient sensing and polarization based on experimentally characterized biochemical mechanisms. The model demonstrates that the known dynamics for Rho GTPase and phosphatidylinositol-3-kinase (PI3K) activation are sufficient for both gradient sensing and polarization. In particular, the model demonstrates that these mechanisms can correctly localize the “front” and “rear” pathways in response to both uniform concentrations and gradients of chemical attractants, including in actin-inhibited cells. Furthermore, the model predictions are robust to the values of many parameters. A key result of the model is the proposed coincidence circuit involving PI3K and Ras that obviates the need for the “global inhibitors” proposed, though never experimentally verified, in many previous mathematical models of eukaryotic chemotaxis. Finally, experiments are proposed to (in)validate this model and further our understanding of neutrophil chemotaxis. Neutrophils target sites of infection and inflammation by sensing chemical signals produced by damaged tissue and infecting microbes and then move in the direction where their concentration is greatest. An open question is how neutrophils integrate this information to determine the direction of motility. We present a mathematical model for the intracellular signaling network regulating polarization and chemotaxis in neutrophils. We demonstrate how the activation of two antagonizing pathways robustly establishes the front and back of the migrating cell. The model is able to reproduce a number of experimental studies, and new experiments are proposed to test different aspects of the model. A key result is the characterization of a coincidence circuit involving phosphatidylinositol-3-kinase (PI3K) and Ras. We demonstrate that this circuit plays a critical role in selectively localizing F-actin to the front of the cell and actomyosin complexes to the rear. As directed motility in response to chemical cues is critical in a number of processes including wound healing and tumor metastasis, the results and insights gained from the model may be applicable to other cell types and organisms.