天然免疫细胞内毒素耐受和致敏的网络拓扑和动力学
Network Topologies and Dynamics Leading to Endotoxin Tolerance and Priming in Innate Immune Cells
摘要：
先天免疫系统作为宿主防御的第一道防线，通过复杂的细胞内和细胞间信号网络感知和适应外来挑战。内毒素耐受性和由巨噬细胞引发的引发是先天免疫细胞复杂适应的经典例子。在反复暴露于不同剂量的细菌内毒素（脂多糖）或其他刺激物时，与单次暴露于刺激物相比，巨噬细胞显示出抑制或增强的炎症反应。内毒素耐受和启动在免疫稳态和多种炎性疾病的发病机制中均起关键作用。然而，其潜在的分子机制还不清楚。通过一个粗粒度的三节点网络的参数空间的计算搜索与两阶段的Metropolis抽样方法，我们列举了所有的网络拓扑结构，可以产生启动或宽容。我们发现了三个主要的引发机制（途径协同作用，抑制剂失活，激活诱导）和一个耐受性（抑制剂持久性）。这些结果不仅解释了现有的实验观察，但也揭示了有趣的测试方案，为未来的实验研究，以澄清内毒素引发和耐受的机制。
英文摘要：
The innate immune system, acting as the first line of host defense, senses and adapts to foreign challenges through complex intracellular and intercellular signaling networks. Endotoxin tolerance and priming elicited by macrophages are classic examples of the complex adaptation of innate immune cells. Upon repetitive exposures to different doses of bacterial endotoxin (lipopolysaccharide) or other stimulants, macrophages show either suppressed or augmented inflammatory responses compared to a single exposure to the stimulant. Endotoxin tolerance and priming are critically involved in both immune homeostasis and the pathogenesis of diverse inflammatory diseases. However, the underlying molecular mechanisms are not well understood. By means of a computational search through the parameter space of a coarse-grained three-node network with a two-stage Metropolis sampling approach, we enumerated all the network topologies that can generate priming or tolerance. We discovered three major mechanisms for priming (pathway synergy, suppressor deactivation, activator induction) and one for tolerance (inhibitor persistence). These results not only explain existing experimental observations, but also reveal intriguing test scenarios for future experimental studies to clarify mechanisms of endotoxin priming and tolerance.
机构、总结、中文摘要均由AI分析而来，可能存在错误，请以论文正文为准。
