溶血磷脂酰甘油导致调节T细胞线粒体功能障碍参与哮喘炎症机制研究

Tregs的数量、功能异常参与哮喘发病。脂质代谢调控免疫。课题组前期应用代谢组学方法发现哮喘患者血清溶血磷脂酰甘油（LPG）水平升高，并与嗜酸粒细胞炎症相关。动物实验显示 LPG导致过敏性哮喘小鼠模型肺组织CD4+Foxp3+Tregs比例降低。体外实验显示LPG抑制naïve CD4+T细胞向Tregs方向分化并引起iTregs抑制功能下降。LPG导致Tregs数量和功能异常的机制尚不明确。线粒体功能对于Tregs数量、功能至关重要。预实验显示：相对于健康者，哮喘患者iTregs存在线粒体损伤且线粒体自噬水平较高；LPG会造成iTregs的线粒体损伤，并增加iTregs的线粒体自噬。本课题将证明如下假说：LPG通过引起Tregs线粒体功能障碍，抑制Tregs的数量和功能，参与哮喘炎症。了解脂质代谢对Tregs的调控机制将为哮喘机制提供新的视角，为哮喘免疫治疗提供新靶点。

Abnormal number or function of Tregs is involved in the pathogenesis of asthma.Lipid metabolism regulates immune cells.Using metabolomics methods,we found that the serum lysophosphatidylglycerol（LPG）level was increased in patients with asthma, which was correlated to eosinophilic inflammation. Animal experiments showed that LPG reduced the proportion of CD4+Foxp3+Tregs in lung tissues of allergic asthmatic mouse. In vitro studies, LPG inhibited differentiation of naïve CD4+ T cells towards Tregs, and LPG caused a decrease in the inhibitory function of iTregs. The mechanism by which LPG leads to the abnormal number and function of Tregs is still unclear. Mitochondrial function is crucial to the number and function of Tregs. Our previous study showed that compared with healthy subjects, iTregs of asthma patients had mitochondrial damage and higher levels of mitophagy, and LPG could cause mitochondrial damage of iTregs and enhance the mitophagy of iTregs. This project will prove the hypothesis that LPG participates in asthma inflammation by causing mitochondrial dysfunction of Tregs and inhibiting the number and function of Tregs. Understanding how lipid metabolism regulates Tregs will provide new insights into the immune mechanism of asthma and provide new targets for asthma immunotherapy.