树突状细胞Wntless-AhR轴对过敏性哮喘作用机制的研究

Asthma is a common respiratory disease. In recent decades, the incidence of allergic asthma has doubled, but the cause is unknown. More and more studies have shown that environmental pollution may be an important risk factor for the rising incidence of allergic asthma. Air pollutants polycyclic aromatic hydrocarbons (PAHs) in the environment can significantly affect the immune system of the body, thereby affecting the immune function of lung tissue and aggravating asthma. Our previous studies have shown that the Wntless-AhR axis can regulate the maturation and activation of dendritic cells (DC), and AhR has been proved to be a receptor of various PAHs. Therefore, the hypothesis that PAHs can induce or aggravate allergic asthma via Wntless-AhR axis is put forward for the first time in this study. It is proposed that the established DC-specific Wntless and AhR gene knockout mice will be used to investigate whether PAHs can affect the differentiation and function of DC through Wntless-AhR axis signaling pathway, thereby inducing or aggravating asthma. The occurrence of allergic diseases and elucidation of their mechanism provide a new idea for the study of the pathogenesis of asthma, and also provide a potential target for the treatment and prevention of allergic asthma aggravated by environmental pollutants.

哮喘是一种常见的呼吸系统疾病。近几十年来，过敏性哮喘的发病率成倍增加，但原因不明。越来越多的研究均表明，环境污染可能是过敏性哮喘发病率上升的一个重要危险因素。环境中空气污染物多环芳烃（PAHs）可显著影响机体的免疫系统，进而影响肺组织免疫功能及加重哮喘。我们前期研究显示，Wntless-AhR轴可调控树突细胞（DC）的成熟与活化，而AhR已证明是多种PAHs的受体。因此，本课题首次提出“空气污染物PAHs可经Wntless-AhR轴诱发或加重过敏性哮喘”的假设，拟采用已构建的DC专一性Wntless和AhR基因敲除小鼠，通过PAHs与过敏原暴露诱导的小鼠哮喘模型，探讨PAHs是否通过Wntless-AhR轴信号通路影响DC的分化与功能，从而诱导或加重哮喘等过敏性疾病的发生并阐明其作用机制，为哮喘发病机制的研究提供一个新思路，也为环境污染物加重的过敏性哮喘的治疗和预防提供潜在的靶点。

研究显示长期暴露于大气污染物可能是导致过敏性哮喘发病率升高的诱因或引发哮喘的危险因子，但其致病机制尚不清楚。本项目围绕“环境污染物（PAH）的暴露可通过Wntless-AhR轴作用DC的功能诱导Th2免疫偏移，改变体内免疫反应”这一假说，首先，使用MALDI-TOF质谱法检测环境污染物对肺上皮细胞暴露中抗Wntless免疫沉淀物中相互作用的蛋白质，结果发现Wntless调控细胞膜表面UPR传感蛋白增强ER应激反应。其次，采用OVA+BaP诱导的小鼠过敏性哮喘模型，探讨过敏性哮喘发病与空气污染物PAH（BaP）及Wntless-AhR轴的相关性，研究发现空气污染物PAH（BaP）可通过Wntless-AhR轴信号刺激肺上皮细胞发生了内质网应激而诱导Th2型过敏反应加重哮喘炎症。进一步，我们还研究了芳基烃受体在调控肺组织微环境细胞稳态中的作用机制，结果发现肺棒状细胞细胞特异性AhR敲除小鼠肺部炎症加剧，反映了棒状细胞细的保护机制有缺陷，棒状细胞中AhR信号传导的这种独特特征可能有助于控制呼吸稳态，对抗毒性损伤、炎症和感染。此外，本团队在基于脂质组学分析发现持久性有机污染物四溴联苯醚（BDE-47）暴露改变了小鼠MLFAs的代谢，变化趋势与碳链长度和饱和度有关。项目已发表相关SCI论文2篇，另有一篇正在投稿中；培养博士后1名和研究生2名，已完成项目考核指标。项目研究结果将为临床哮喘的精准诊断提供全新的理论依据和防治方法。