Systems Analysis of the Dynamic Inflammatory Response to Tissue Damage Reveals Spatiotemporal Properties of the Wound Attractant Gradient.
Systems Analysis of the Dynamic Inflammatory Response to Tissue Damage Reveals Spatiotemporal Properties of the Wound Attractant Gradient.
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DOI：
10.1016/j.cub.2016.06.012
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发表时间：
2016-08-08
期刊：
影响因子：
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通讯作者：
Stumpf MPH
中科院分区：
文献类型：
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作者：
Weavers H;Liepe J;Sim A;Wood W;Martin P;Stumpf MPH
在组织损伤后的急性炎症阶段，先天免疫系统的细胞通过在伤口部位释放的促炎介质快速募集到损伤部位。尽管活体成像的进步使我们能够直接在体内可视化这一过程，但原发性免疫损伤引诱剂的确切身份和性质仍不清楚，因为目前不可能直接观察和准确测量组织中的这些信号。在这里，我们证明了有关引诱信号的详细信息可以直接从响应免疫细胞的体内行为中提取。通过应用基于推理的计算方法来分析果蝇炎症反应的体内动力学，我们获得了新的详细了解吸引剂梯度的时空特性。特别是，我们表明，伤口引诱释放的伤口边缘细胞，而不是由受伤的组织本身，它扩散远离这个来源的速度远远低于以前牵连的信号，如H2 O2和ATP，排除这些快速介质作为主要的化学引诱。然后，我们预测，并通过实验测试，竞争引诱信号如何在空间和时间上相互作用，以调节愈合伤口复杂环境中的多步细胞导航，揭示了最初暴露于损伤引诱剂后的受体脱敏期。将我们的分析扩展到模拟更大的伤口，我们发现了体内反应免疫细胞的动态行为变化，这是伤口随后是否愈合的预测。应用对组织损伤的体内炎症反应的计算建模。该模型推断了伤口吸引剂梯度的新时空特性。伤口信号从伤口边缘释放30 min并以200 μm2/min的速度扩散。使用贝叶斯模型的炎症反应组织损伤的果蝇提取新的时空属性的伤口引诱剂，包括其扩散系数，持续时间和信号产生的来源。模拟对两种竞争吸引物的反应揭示了免疫细胞脱敏的一段时间。
In the acute inflammatory phase following tissue damage, cells of the innate immune system are rapidly recruited to sites of injury by pro-inflammatory mediators released at the wound site. Although advances in live imaging allow us to directly visualize this process in vivo, the precise identity and properties of the primary immune damage attractants remain unclear, as it is currently impossible to directly observe and accurately measure these signals in tissues. Here, we demonstrate that detailed information about the attractant signals can be extracted directly from the in vivo behavior of the responding immune cells. By applying inference-based computational approaches to analyze the in vivo dynamics of the Drosophila inflammatory response, we gain new detailed insight into the spatiotemporal properties of the attractant gradient. In particular, we show that the wound attractant is released by wound margin cells, rather than by the wounded tissue per se, and that it diffuses away from this source at rates far slower than those of previously implicated signals such as H2O2 and ATP, ruling out these fast mediators as the primary chemoattractant. We then predict, and experimentally test, how competing attractant signals might interact in space and time to regulate multi-step cell navigation in the complex environment of a healing wound, revealing a period of receptor desensitization after initial exposure to the damage attractant. Extending our analysis to model much larger wounds, we uncover a dynamic behavioral change in the responding immune cells in vivo that is prognostic of whether a wound will subsequently heal or not. Computational modeling of in vivo inflammatory response to tissue damage is applied The model infers novel spatiotemporal properties of the wound attractant gradient Wound signal is released from the wound edge for 30 min and diffuses at 200 μm2/min Modeling two competing wounds reveals a period of immune cell desensitization Weavers et al. use Bayesian modeling of the inflammatory response to tissue damage in Drosophila to extract novel spatiotemporal properties of the wound attractant, including its diffusion coefficient, duration, and source of signal production. Modeling the response to two competing attractants uncovers a period of immune cell desensitization.