LPG 18:0 是哮喘的通用生物标志物，抑制调节性 T 细胞的分化和功能
2025/01/06
摘要
背景：哮喘的诊断、严重程度评估以及治疗策略的制定是疾病管理的重要环节。鉴于生物标志物在疾病管理中的可靠性，本研究旨在识别并探索与哮喘相关的生物标志物，并研究其作用机制。
方法：采用脂质组学方法分析哮喘患者和对照组血清中的甘油磷脂谱。测定不同哮喘亚型中溶血磷脂酰甘油（LPG）18:0的绝对浓度。利用小鼠哮喘模型验证其作为生物标志物的潜力，并研究在体内的作用机制。通过流式细胞术在体外评估LPG 18:0对CD4+ T细胞分化、增殖和凋亡的影响，同时通过线粒体膜电位、活性氧和ATP产量测定来评估线粒体功能障碍。使用小分子抑制剂研究LPG 18:0在调节性T细胞（Tregs）中的细胞内机制。
结果：哮喘患者与对照组的血清甘油磷脂谱存在差异，其中哮喘患者血清中LPG 18:0水平显著升高，且与哮喘的严重程度和控制水平相关。体内和体外研究表明，LPG 18:0阻碍了初始CD4+ T细胞向Tregs的分化，并损害了其抑制功能。进一步研究发现，在Treg分化过程中，LPG 18:0通过SIRT1介导的去乙酰化作用降低了FOXP3蛋白水平。
结论：本研究发现哮喘患者血清中LPG 18:0水平普遍升高，可作为哮喘的生物标志物。LPG 18:0通过NAD+/SIRT1/FOXP3通路损害Treg功能。我们的研究揭示了LPG 18:0作为哮喘生物标志物的潜力，并阐明了其在哮喘诊断和治疗中的作用。
LPG 18:0 is a general biomarker of asthma and inhibits the differentiation and function of regulatory T-cells
Abudureyimujiang Aili, Yuqing Wang, Ying Shang, Lijiao Zhang, Huan Liu, Zemin Li, Lixiang Xue, Yahong Chen, Yongchang Sun, Xu Zhang, Rong Jin, Chun Chang.
Eur Respir J. 2024 Dec; 64 (6). doi: 10.1183/13993003.01752-2023
Abstract
BACKGROUND: The diagnosis, severity assessment, and development of therapeutic strategies for asthma are crucial aspects of disease management. Since biomarkers are reliable tools in disease management, we aimed to identify and explore asthma-associated biomarkers and investigate their mechanisms.
METHODS: Lipidomics was used to profile serum glycerophospholipids in asthmatic patients and controls. The absolute concentration of lysophosphatidylglycerol (LPG) 18:0 was quantified in various asthma subtypes. Mouse asthma models were used to confirm its potential as a biomarker and investigate its mechanisms in vivo. The effects of LPG 18:0 on CD4+ T-cell differentiation, proliferation and apoptosis were assessed in vitro by flow cytometry, while mitochondrial dysfunction was evaluated through mitochondrial membrane potential, reactive oxygen species and ATP production measurements. The intracellular mechanism of LPG 18:0 in regulatory T-cells (Tregs) was investigated using small-molecule inhibitors.
RESULTS: The serum glycerophospholipid profile varied between asthmatic patients and control group, with LPG 18:0 levels being notably higher in asthmatic patients, correlating with asthma severity and control level. In vivo and in vitro studies revealed that LPG 18:0 impaired naïve CD4+ T-cell differentiation into Tregs and compromised their suppressive function. Further investigation demonstrated that LPG 18:0 treatment reduced the FOXP3 protein level via SIRT1-mediated deacetylation during Treg differentiation.
CONCLUSIONS: This study identifies that serum levels of LPG 18:0 are generally elevated in asthmatics and serve as a biomarker for asthma. LPG 18:0 impairs Treg function via the NAD+/SIRT1/FOXP3 pathway. Our research reveals the potential of LPG 18:0 as a biomarker for asthma, elucidating its role in asthma diagnosis and treatment.
背景：哮喘的诊断、严重程度评估以及治疗策略的制定是疾病管理的重要环节。鉴于生物标志物在疾病管理中的可靠性，本研究旨在识别并探索与哮喘相关的生物标志物，并研究其作用机制。
方法：采用脂质组学方法分析哮喘患者和对照组血清中的甘油磷脂谱。测定不同哮喘亚型中溶血磷脂酰甘油（LPG）18:0的绝对浓度。利用小鼠哮喘模型验证其作为生物标志物的潜力，并研究在体内的作用机制。通过流式细胞术在体外评估LPG 18:0对CD4+ T细胞分化、增殖和凋亡的影响，同时通过线粒体膜电位、活性氧和ATP产量测定来评估线粒体功能障碍。使用小分子抑制剂研究LPG 18:0在调节性T细胞（Tregs）中的细胞内机制。
结果：哮喘患者与对照组的血清甘油磷脂谱存在差异，其中哮喘患者血清中LPG 18:0水平显著升高，且与哮喘的严重程度和控制水平相关。体内和体外研究表明，LPG 18:0阻碍了初始CD4+ T细胞向Tregs的分化，并损害了其抑制功能。进一步研究发现，在Treg分化过程中，LPG 18:0通过SIRT1介导的去乙酰化作用降低了FOXP3蛋白水平。
结论：本研究发现哮喘患者血清中LPG 18:0水平普遍升高，可作为哮喘的生物标志物。LPG 18:0通过NAD+/SIRT1/FOXP3通路损害Treg功能。我们的研究揭示了LPG 18:0作为哮喘生物标志物的潜力，并阐明了其在哮喘诊断和治疗中的作用。
(四川大学华西医院呼吸与危重症医学科 邓稞1 王霁1 王刚1 译)
(Eur Respir J. 2024 Dec; 64 (6). doi: 10.1183/13993003.01752-2023)
(Eur Respir J. 2024 Dec; 64 (6). doi: 10.1183/13993003.01752-2023)
LPG 18:0 is a general biomarker of asthma and inhibits the differentiation and function of regulatory T-cells
Abudureyimujiang Aili, Yuqing Wang, Ying Shang, Lijiao Zhang, Huan Liu, Zemin Li, Lixiang Xue, Yahong Chen, Yongchang Sun, Xu Zhang, Rong Jin, Chun Chang.
Eur Respir J. 2024 Dec; 64 (6). doi: 10.1183/13993003.01752-2023
Abstract
BACKGROUND: The diagnosis, severity assessment, and development of therapeutic strategies for asthma are crucial aspects of disease management. Since biomarkers are reliable tools in disease management, we aimed to identify and explore asthma-associated biomarkers and investigate their mechanisms.
METHODS: Lipidomics was used to profile serum glycerophospholipids in asthmatic patients and controls. The absolute concentration of lysophosphatidylglycerol (LPG) 18:0 was quantified in various asthma subtypes. Mouse asthma models were used to confirm its potential as a biomarker and investigate its mechanisms in vivo. The effects of LPG 18:0 on CD4+ T-cell differentiation, proliferation and apoptosis were assessed in vitro by flow cytometry, while mitochondrial dysfunction was evaluated through mitochondrial membrane potential, reactive oxygen species and ATP production measurements. The intracellular mechanism of LPG 18:0 in regulatory T-cells (Tregs) was investigated using small-molecule inhibitors.
RESULTS: The serum glycerophospholipid profile varied between asthmatic patients and control group, with LPG 18:0 levels being notably higher in asthmatic patients, correlating with asthma severity and control level. In vivo and in vitro studies revealed that LPG 18:0 impaired naïve CD4+ T-cell differentiation into Tregs and compromised their suppressive function. Further investigation demonstrated that LPG 18:0 treatment reduced the FOXP3 protein level via SIRT1-mediated deacetylation during Treg differentiation.
CONCLUSIONS: This study identifies that serum levels of LPG 18:0 are generally elevated in asthmatics and serve as a biomarker for asthma. LPG 18:0 impairs Treg function via the NAD+/SIRT1/FOXP3 pathway. Our research reveals the potential of LPG 18:0 as a biomarker for asthma, elucidating its role in asthma diagnosis and treatment.
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