DataSheet2_Computational inference of chemokine-mediated roles for the vagus nerve in modulating intra- and inter-tissue inflammation.PDF

Introduction: The vagus nerve innervates multiple organs, but its role in regulating cross-tissue spread of inflammation is as yet unclear. We hypothesized that the vagus nerve may regulate cross-tissue inflammation via modulation of the putatively neurally regulated chemokine IP-10/CXCL10.
Methods: Rate-of-change analysis, dynamic network analysis, and dynamic hypergraphs were used to model intra- and inter-tissue trends, respectively, in inflammatory mediators from mice that underwent either vagotomy or sham surgery.
Results: This analysis suggested that vagotomy primarily disrupts the cross-tissue attenuation of inflammatory networks involving IP-10 as well as the chemokines MIG/CXCL9 and CCL2/MCP-1 along with the cytokines IFN-γ and IL-6. Computational analysis also suggested that the vagus-dependent rate of expression of IP-10 and MIG/CXCL9 in the spleen impacts the trajectory of chemokine expression in other tissues. Perturbation of this complex system with bacterial lipopolysaccharide (LPS) revealed a vagally regulated role for MIG in the heart. Further, LPS-stimulated expression of IP-10 was inferred to be vagus-independent across all tissues examined while reducing connectivity to IL-6 and MCP-1, a hypothesis supported by Boolean network modeling.
Discussion: Together, these studies define novel spatiotemporal dimensions of vagus-regulated acute inflammation.

引言：迷走神经支配多个器官，但其在调控炎症跨组织扩散中的作用目前尚不明确。本研究提出假说：迷走神经可通过调控推测受神经调控的趋化因子IP-10/CXCL10，实现对炎症跨组织扩散的调控。
方法：本研究分别采用变化率分析、动态网络分析及动态超图，对接受迷走神经切断术或假手术的小鼠体内炎症介质的组织内及组织间变化趋势开展建模分析。
结果：本分析结果表明，迷走神经切断术主要破坏了以IP-10/CXCL10、趋化因子MIG/CXCL9与CCL2/MCP-1，以及细胞因子干扰素-γ（IFN-γ）和白细胞介素6（IL-6）为核心的炎症网络的跨组织衰减效应。计算分析进一步显示，脾脏内IP-10与MIG/CXCL9的迷走神经依赖性表达速率，会影响其他组织中趋化因子的表达轨迹。通过细菌脂多糖（LPS）对该复杂系统进行扰动实验后，研究人员发现MIG在心脏中发挥迷走神经调控的作用。此外，经布尔网络建模验证的假说显示，在所有检测组织中，LPS刺激诱导的IP-10表达均不依赖迷走神经，且该过程会降低IP-10与IL-6、MCP-1的关联强度。
讨论：综上，本研究阐明了迷走神经调控急性炎症的新型时空维度。