Center of Allergy and Environment, Technical University of Munich and Helmholtz Zentrum München, Munich, Germany.
Center of Allergy and Environment, Technical University of Munich and Helmholtz Zentrum München, Munich, Germany; Department of Otolaryngology, Allergy Section, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
J Allergy Clin Immunol. 2021 Feb;147(2):587-599. doi: 10.1016/j.jaci.2020.04.064. Epub 2020 Jun 12.
Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is a chronic inflammatory condition, which is driven by an aberrant arachidonic acid metabolism. Macrophages are major producers of arachidonic acid metabolites and subject to metabolic reprogramming, but they have been neglected in N-ERD.
This study sought to elucidate a potential metabolic and epigenetic macrophage reprogramming in N-ERD.
Transcriptional, metabolic, and lipid mediator profiles in macrophages from patients with N-ERD and healthy controls were assessed by RNA sequencing, Seahorse assays, and LC-MS/MS. Metabolites in nasal lining fluid, sputum, and plasma from patients with N-ERD (n = 15) and healthy individuals (n = 10) were quantified by targeted metabolomics analyses. Genome-wide methylomics were deployed to define epigenetic mechanisms of macrophage reprogramming in N-ERD.
This study shows that N-ERD monocytes/macrophages exhibit an overall reduction in DNA methylation, aberrant metabolic profiles, and an increased expression of chemokines, indicative of a persistent proinflammatory activation. Differentially methylated regions in N-ERD macrophages included genes involved in chemokine signaling and acylcarnitine metabolism. Acylcarnitines were increased in macrophages, sputum, nasal lining fluid, and plasma of patients with N-ERD. On inflammatory challenge, N-ERD macrophages produced increased levels of acylcarnitines, proinflammatory arachidonic acid metabolites, cytokines, and chemokines as compared to healthy macrophages.
Together, these findings decipher a proinflammatory metabolic and epigenetic reprogramming of macrophages in N-ERD.
非甾体抗炎药加重的呼吸道疾病（N-ERD）是一种慢性炎症性疾病，其由异常的花生四烯酸代谢驱动。巨噬细胞是花生四烯酸代谢物的主要产生者，并受到代谢重编程的影响，但它们在 N-ERD 中被忽视了。
本研究旨在阐明 N-ERD 中潜在的代谢和表观遗传巨噬细胞重编程。
通过 RNA 测序、 Seahorse 测定和 LC-MS/MS 评估 N-ERD 患者和健康对照者巨噬细胞的转录、代谢和脂质介质谱。通过靶向代谢组学分析定量测定 N-ERD 患者（n=15）和健康个体（n=10）的鼻衬液、痰和血浆中的代谢物。采用全基因组甲基化组学来定义 N-ERD 中巨噬细胞重编程的表观遗传机制。
本研究表明，N-ERD 单核细胞/巨噬细胞表现出总体 DNA 甲基化减少、代谢谱异常和趋化因子表达增加，表明持续的促炎激活。N-ERD 巨噬细胞中的差异甲基化区域包括参与趋化因子信号和酰基辅酶 A 代谢的基因。N-ERD 巨噬细胞、痰、鼻衬液和血浆中的酰基辅酶 A 增加。在炎症刺激下，与健康巨噬细胞相比，N-ERD 巨噬细胞产生更多的酰基辅酶 A、促炎花生四烯酸代谢物、细胞因子和趋化因子。
这些发现共同揭示了 N-ERD 中巨噬细胞的促炎代谢和表观遗传重编程。
