Inflammatory macrophage memory in nonsteroidal anti-inflammatory drug–exacerbated respiratory disease - 04/02/21
Abstract |
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.
Il testo completo di questo articolo è disponibile in PDF.Graphical abstract |
Key words : Acylcarnitines, chemokines, eicosanoids, lipid mediator, macrophages, metabolomics, nasal polyps, NSAID-exacerbated respiratory disease, trained immunity, type 2 inflammation
Abbreviations used : AA, aMDM, BMI, CRSwNP, DEG, DMR, LOX, LT, N-ERD, NSAID, NT, PG, PUFA, RNAseq, sMac
Mappa
| This study was supported by the Else Kröner-Fresenius-Stiftung (grant 2015_A195), the German Research Foundation (FOR2599, ES 471/3-1), the Fritz Thyssen Stiftung (grant Az. 10.17.2.017MN), and a Helmholtz Young Investigator grant (VH-NG-1331) to JEvB. CSW receives grant support by the German Center for Lung Research (82DZL00302). This study was supported in part by a grant from the German Federal Ministry of Education and Research to the German Center Diabetes Research. |
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| Disclosure of potential conflict of interest: C. B. Schmidt-Weber received grant support from Allergopharma, PLS Design, as well as Zeller AG; and received speaker honoraria from Allergopharma. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 147 - N° 2
P. 587-599 - Febbraio 2021 Ritorno al numero
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