神经活动能够对免疫系统产生重要影响，但是神经信号对特定免疫器官及其相关免疫反应的调控机制仍有待阐明。申请人课题组的最新工作开发了ImmuView技术，在领域内首次实现对未经切片处理的多种免疫器官进行全组织免疫染色和三维荧光成像。利用这一先进成像技术，首次发现在脾脏中存在独特的、呈花序状分布的交感神经网络。进一步研究表明，局部交感神经在脾脏对抗细菌感染的天然免疫中起到负调控功能。不仅如此，交感神经递质去甲肾上腺素能够特异性作用于Beta2-肾上腺素受体抑制天然免疫反应。基于以上重要研究成果，本申请项目将阐明脾脏内交感神经可塑性变化的分子机制及其在调控天然免疫中的重要功能。具体研究将按照三个方向开展：1、不同刺激条件下脾脏交感神经的可塑性变化；2、脾脏交感神经可塑性变化的分子机制；3、脾脏交感神经可塑性变化在调控天然免疫中的生理功能。本申请项目的研究将有力推进对于神经-免疫互作机制的深入认识。

The nervous system can modulate the body's immunity. However, how efferent neural signals reach out to control specific immune organs, as well as their corresponding immune responses, remains incompletely characterized. In our recent work, we developed the ImmuView technique for robust whole-tissue immunolabeling and 3D assessment of neural innervations in the intact, unsectioned mouse immune organs for the first time in the field. This advanced imaging technique revealed the unique presence of a panicle-shaped sympathetic architecture in the spleen but not other classic immune organs including bone marrow, lymph nodes or thymus. Moreover, we showed that such sympathetic innervations in the spleen negatively modulated the anti-bacteria innate immunity, and the neurotransmitter norepinephrine was sufficient for this inhibitory function by acting cell-intrinsically via β2-adrenergic receptor. Based on these important findings, this grant application is aimed to elucidate the molecular mechanism underlying plasticity of the spleen sympathetic innervations and its key modulative function in innate immunity. The proposed research will be carried out as follow: (1) Neural plasticity of the spleen sympathetic innervations under different conditions; (2) Molecular mechanism regulating plasticity of the spleen sympathetic innervations; (3) Key role of such plasticity of the spleen sympathetic innervations in modulating innate immune response. Results obtained from this proposal will significantly promote our in-depth understanding of the physiology of neuro-immune interplay.