Inflammatory macrophage memory in nonsteroidal anti-inflammatory drug–exacerbated respiratory disease,Journal of Allergy and Clinical Immunology

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Inflammatory macrophage memory in nonsteroidal anti-inflammatory drug–exacerbated respiratory disease
Journal of Allergy and Clinical Immunology ( IF 11.4 ) Pub Date : 2020-06-12 , DOI: 10.1016/j.jaci.2020.04.064
Pascal Haimerl ₁ , Ulrike Bernhardt ₂ , Sonja Schindela ₁ , Fiona D R Henkel ₁ , Antonie Lechner ₁ , Ulrich M Zissler ₁ , Xavier Pastor ₃ , Dominique Thomas ₄ , Alexander Cecil ₅ , Yan Ge ₆ , Mark Haid ₅ , Cornelia Prehn ₅ , Janina Tokarz ₇ , Matthias Heinig ₃ , Jerzy Adamski ₈ , Carsten B Schmidt-Weber ₁ , Adam M Chaker ₂ , Julia Esser-von Bieren ₁

Affiliation

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.
Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.
Pharmazentrum Frankfurt/Zentrum für Arzneimittelforschung, -Entwicklung und -Sicherheit (ZAFES), Institute of Clinical Pharmacology, Goethe University Frankfurt, Frankfurt, Germany.
Research Unit of Molecular Endocrinology and Metabolism, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, Germany.
Biotechnology Center Dresden, Technical University of Dresden, Dresden, Germany.
Research Unit of Molecular Endocrinology and Metabolism, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany.
Research Unit of Molecular Endocrinology and Metabolism, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, Germany; Lehrstuhl für Experimentelle Genetik, Technische Universität München, Freising-Weihenstephan, Germany; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Background

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.

Objective

This study sought to elucidate a potential metabolic and epigenetic macrophage reprogramming in N-ERD.

Methods

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.

Results

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.

Conclusions

Together, these findings decipher a proinflammatory metabolic and epigenetic reprogramming of macrophages in N-ERD.

中文翻译：

非甾体抗炎药加重呼吸系统疾病中的炎性巨噬细胞记忆

背景

非甾体抗炎药加重性呼吸系统疾病 (N-ERD) 是一种慢性炎症，由花生四烯酸代谢异常驱动。巨噬细胞是花生四烯酸代谢物的主要生产者，并受代谢重编程的影响，但它们在 N-ERD 中被忽视了。

客观的

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。

方法

来自 N-ERD 患者和健康对照的巨噬细胞的转录、代谢和脂质介质特征通过 RNA 测序、海马分析和 LC-MS/MS 进行评估。来自 N-ERD 患者（n = 15）和健康个体（n = 10）的鼻内衬液、痰液和血浆中的代谢物通过靶向代谢组学分析进行量化。全基因组甲基组学被用于定义 N-ERD 中巨噬细胞重编程的表观遗传机制。

结果

这项研究表明，N-ERD 单核细胞/巨噬细胞表现出 DNA 甲基化、异常代谢谱和趋化因子表达增加的总体减少，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传导和酰基肉碱代谢的基因。N-ERD 患者的巨噬细胞、痰液、鼻腔内膜液和血浆中酰基肉碱含量增加。在炎症刺激下，与健康巨噬细胞相比，N-ERD 巨噬细胞产生的酰基肉碱、促炎花生四烯酸代谢物、细胞因子和趋化因子水平升高。