Adaptive-Control Model for Neutrophil Orientation in the Direction of Chemical Gradients
Adaptive-Control Model for Neutrophil Orientation in the Direction of Chemical Gradients
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DOI：
10.1016/j.bpj.2008.12.3967
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发表时间：
2009-05-20
影响因子：
3.4
通讯作者：
Toner，Mehmet
中科院分区：
文献类型：
--
作者：
Irimia，Daniel;Balazsi，Gabor;Toner，Mehmet
中性粒细胞具有显著的检测趋化物质梯度方向的能力，并在细菌感染和组织损伤时定向移动。由于中性粒细胞在健康和疾病中的作用，人们已经对其进行了广泛的研究，并鉴定了许多参与梯度检测和趋化的信号机制的分子。然而，梯度感应和中性粒细胞定向迁移的细胞尺度机制一直比较难以捉摸，现有的模型对这些过程的了解有限。这里，我们提出了一种我们认为是一种新的自适应控制模型，用于启动细胞极化对梯度的响应。在这个模型中，中性粒细胞首先通过在随机方向上延伸突起来采样环境，然后根据刺激水平的局部时间变化来调整它们的敏感度。我们的结果表明，微管可能通过中性粒细胞内的重新分布，在整合来自细胞外围的所有感觉事件方面发挥关键作用，也可能参与局部信号的调制。一个意想不到的发现是，模型中性粒细胞在激活的时间和方向上表现出显著的随机性，与我们在微流控设备中的实验观察相类似。此外，它们对信号反应的速率和幅度的变化以及对化学诱导剂浓度和空间梯度的大范围的变化都具有很强的响应能力。
Neutrophils have a remarkable ability to detect the direction of chemoattractant gradients and move directionally in response to bacterial infections and tissue injuries. For their role in health and disease, neutrophils have been extensively studied, and many of the molecules involved in the signaling mechanisms of gradient detection and chemotaxis have been identified. However, the cellular-scale mechanisms of gradient sensing and directional neutrophil migration have been more elusive, and existent models provide only limited insight into these processes. Here, we propose a what we believe is a novel adaptive-control model for the initiation of cell polarization in response to gradients. In this model, the neutrophils first sample the environment by extending protrusions in random directions and subsequently adapt their sensitivity depending on localized, temporal changes in stimulation levels. Our results suggest that microtubules may play a critical role in integrating all the sensing events from the cellular periphery through their redistribution inside the neutrophils, and may also be involved in modulating local signaling. An unexpected finding was that model neutrophils exhibit significant randomness in timing and directionality of activation, comparable to our experimental observations in microfluidic devices. Moreover, their responses are robust against alterations of the rate and amplitude of the signaling reactions, and for a broad range in chemoattractant concentrations and spatial gradients.