神经酰胺/鞘氨醇-1-磷酸失衡与未控制哮喘的不同炎症表型相关。

Ceramide/sphingosine-1-phosphate imbalance is associated with distinct inflammatory phenotypes of uncontrolled asthma.

作者信息

Kim Seung-Hyun, Jung Hae-Won, Kim Minji, Moon Ji-Young, Ban Ga-Young, Kim Su Jung, Yoo Hyun-Ju, Park Hae-Sim

机构信息

Translational Research Laboratory for Inflammatory Disease, Clinical Trial Center, Ajou University Medical Center, Suwon, South Korea.

Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, South Korea.

出版信息

Allergy. 2020 Aug;75(8):1991-2004. doi: 10.1111/all.14236. Epub 2020 Mar 12.

DOI:10.1111/all.14236

PMID:32072647

Abstract

BACKGROUND

Asthma is associated with inflammatory dysregulation, but the underlying metabolic signatures are unclear. This study aimed to classify asthma inflammatory phenotypes based on cellular and metabolic features.

METHODS

To determine cellular and metabolic profiles, we assessed inflammatory cell markers using flow cytometry, sphingolipid (SL) metabolites using LC-MS/MS, and serum cytokines using ELISA. Targeted gene polymorphisms were determined to identify genetic predispositions related to the asthma inflammatory phenotype.

RESULTS

In total, 137 patients with asthma and 20 healthy controls (HCs) were enrolled. Distinct cellular and metabolic profiles were found between them; patients with asthma showed increased expressions of inflammatory cell markers and higher levels of SL metabolites compared to HCs (P < .05 for all). Cellular markers (CD66 neutrophils, platelet-adherent eosinophils) and SL metabolic markers (C16:0 and C24:0 ceramides) for uncontrolled asthma were also identified; higher levels were observed in uncontrolled asthma compared to controlled asthma (P < .05 for all). Asthmatics patients with higher levels of CD66 neutrophils had lower FEV1(%), higher ACQ (but lower AQLO) scores, and higher sphingosine and C16:0 ceramide levels compared to those with low levels of CD66 neutrophils. Asthmatics patients with higher levels of platelet-adherent eosinophils had higher S1P levels compared to those with lower levels of platelet-adherent eosinophils. Patients carrying TT genotype of ORMDL3 had more CD66 neutrophils; those with AG/ GG genotypes of SGMS1 exhibited higher platelet-adherent eosinophils.

CONCLUSION

Patients with uncontrolled asthma possess distinct inflammatory phenotypes including increased CD66 neutrophils and platelet-adherent eosinophils, with an imbalanced ceramide/S1P rheostat, potentially involving ORMDL3 and SGMS1 gene polymorphisms. Ceramide/S1P synthesis could be targeted to control airway inflammation.

摘要

背景

哮喘与炎症调节异常相关，但其潜在的代谢特征尚不清楚。本研究旨在基于细胞和代谢特征对哮喘炎症表型进行分类。

方法

为了确定细胞和代谢谱，我们使用流式细胞术评估炎症细胞标志物，使用液相色谱 - 串联质谱法评估鞘脂（SL）代谢物，使用酶联免疫吸附测定法评估血清细胞因子。通过测定靶向基因多态性来确定与哮喘炎症表型相关的遗传易感性。

结果

共纳入137例哮喘患者和20名健康对照（HC）。发现他们之间存在明显的细胞和代谢谱差异；与HC相比，哮喘患者炎症细胞标志物表达增加，SL代谢物水平更高（所有P < 0.05）。还确定了未控制哮喘的细胞标志物（CD66中性粒细胞、血小板黏附嗜酸性粒细胞）和SL代谢标志物（C16:0和C24:0神经酰胺）；与控制良好的哮喘相比，未控制哮喘中这些标志物水平更高（所有P < 0.05）。与CD66中性粒细胞水平低的哮喘患者相比，CD66中性粒细胞水平高的哮喘患者FEV1（%）更低，ACQ（但AQLO更低）评分更高，鞘氨醇和C16:0神经酰胺水平更高。与血小板黏附嗜酸性粒细胞水平低的哮喘患者相比，血小板黏附嗜酸性粒细胞水平高的哮喘患者S1P水平更高。携带ORMDL3基因TT基因型的患者有更多的CD66中性粒细胞；携带SGMS1基因AG / GG基因型的患者表现出更高的血小板黏附嗜酸性粒细胞。