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Haimerl, P. ; Bernhardt, U. ; Schindela, S. ; Henkel, F. ; Lechner, A. ; Zissler, U.M. ; Pastor, X. ; Thomas, D.* ; Cecil, A. ; Ge, Y.* ; Haid, M. ; Prehn, C. ; Tokarz, J. ; Heinig, M. ; Adamski, J. ; Schmidt-Weber, C.B. ; Chaker, A. ; Esser-von Bieren, J.

Inflammatory macrophage memory in nonsteroidal anti-inflammatory drug–exacerbated respiratory disease.

J. Allergy Clin. Immunol. 147, 587-599 (2020)
Publ. Version/Full Text Postprint DOI PMC
Open Access Green
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Acylcarnitines ; Chemokines ; Eicosanoids ; Lipid Mediator ; Macrophages ; Metabolomics ; Nasal Polyps ; Nsaid-exacerbated Respiratory Disease ; Trained Immunity ; Type 2 Inflammation
ISSN (print) / ISBN 0091-6749
e-ISSN 1097-6825
Journal The journal of allergy and clinical immunology
Quellenangaben Volume: 147, Issue: 2, Pages: 587-599 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Amsterdam [u.a.]
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute for Allergy Research (IAF)
Institute of Computational Biology (ICB)
Molekulare Endokrinologie und Metabolismus (MEM)
Grants German Federal Ministry of Education and Research
German Center for Lung Research
Helmholtz Young Investigator grant
Fritz Thyssen Stiftung
German Research Foundation
Else Kroner-Fresenius-Stiftung