神经肽Y在应激与过敏性支气管哮喘关系中的心理神经免疫学研究

Neuropeptide Y (NPY) buffers against the effect of psychological stress on asthma, but the underlying mechanism remains unclear. In early 2016, a paper published in Science reported that pulmonary neuroendocrine cells function as airway sensors to control lung immune response, inferring the potential pivotal role of neuropeptides in asthma. Our previous study (Journal of Allergy and Clinical Immunology, 2015) showed that NPY is a predictor of the persistent Th2 inflammatory response in patients with asthma. On the basis of our previous findings, the current study aims to further identify the mechanism of NPY in mediating the effects of psychological stress on asthma. Allergic asthma and stress models will be established in mice. Spatial expression pattern of NPY and its Y1 receptor in asthmatic airways will be determined. We will investigate the role of NPY in the pathogenesis of asthma including Th1/Th2 imbalance, Th17, as well as ILC2 immune response. The impact of NPY on macrophage and the underlying pathway will be identified. Meanwhile, results derived from the mouse study will be further verified in patients under asthma attack or with stable asthma. This study contributes to the understanding of the interaction between the neuroendocrine system and the immune system, and may also reveal the potential therapeutic effect of NPY agonists in asthma via the modulation of the immune response.

神经肽Y（neuropeptide Y, NPY）可缓冲心理应激对哮喘的影响，然而相关机制尚不明确。2016年《Science》对肺神经内分泌细胞作为传感器调节肺部免疫反应的报导启示神经肽在哮喘中的重要作用。申请者前期研究（Journal of Allergy and Clinical Immunology，2015）发现，NPY预测哮喘患者的长期Th2炎性反应。在此基础上，本项目旨进一步揭示NPY介导应激对哮喘影响的机制。拟建立过敏性哮喘与应激小鼠模型，检测NPY与Y1R的表达和分布，考察NPY对哮喘发病机制包括Th1/Th2、Th17和ILC2免疫应答的影响，及其作用于巨噬细胞影响哮喘的可能通路。小鼠实验结果将在急性哮喘发作组和稳定期哮喘组病人中进行验证。本研究有助于对神经内分泌免疫交互作用的进一步理解，并可能揭示NPY激动剂通过免疫调节对哮喘的潜在治疗作用。

该项目旨在确立心理应激、神经肽Y及其受体和支气管哮喘的关系，为支气管哮喘的预防、治疗和护理提供坚实的心理学和神经科学理论依据，揭示神经肽Y介导心理应激对哮喘影响的免疫机制。课题组成员严格按照项目目标和计划，开展了大量的实验和临床研究工作，考察了急性期发作和稳定期哮喘患者的心理应激、抑郁和焦虑等心理健康状况，创新性的建立了大鼠慢性心理应激模型，对相关行为学指标进行了测定，并测量了外周和中枢相关炎症因子的水平，以探明炎症在慢性应激形成和逆转中的关键作用，验证降低中枢和外周炎症水平是否可作为相关治疗的靶点。同时，我们定义了病理(pathogenic Th2) Th2细胞，测量了该细胞亚型和II型天然免疫细胞(group II innate lymphoid cells, ILC2)对哮喘的发病和不同病程的影响。我们利用临床指标、多种免疫细胞亚群(Th1、Th2、Th17、Treg、TFH及相关细胞分化和亚型比率)检测，以及相关趋化因子和炎症因子的表达系统地表征了Th2-高和非Th2哮喘亚型。对神经肽Y及其受体在心理应激和哮喘关系中的作用进行了分析，测试了神经肽Y与哮喘临床指标和疾病状态、不同免疫细胞亚型等的关联，以及在一年的被试追踪过程中的动态变化趋势。研究结果丰硕，在本领域高影响因子的权威杂志上发表了5篇SCI论文，受邀发表了1篇其它类型的英文论文，课题主持人被授予自然研究会青年研究者奖(2018 Nature Research Society Young Scholar Award)，培养了3名博士研究生，顺利完成了课题项目计划，为呼吸系统疾病的医疗实践和公共卫生政策的制定奠定了进一步的基础。