Pascal Haimerl1, Ulrike Bernhardt2, Sonja Schindela1, Fiona D R Henkel1, Antonie Lechner1, Ulrich M Zissler1, Xavier Pastor3, Dominique Thomas4, Alexander Cecil5, Yan Ge6, Mark Haid5, Cornelia Prehn5, Janina Tokarz7, Matthias Heinig3, Jerzy Adamski8, Carsten B Schmidt-Weber1, Adam M Chaker2, Julia Esser-von Bieren9. 1. Center of Allergy and Environment, Technical University of Munich and Helmholtz Zentrum München, Munich, Germany. 2. 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. 3. Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany. 4. Pharmazentrum Frankfurt/Zentrum für Arzneimittelforschung, -Entwicklung und -Sicherheit (ZAFES), Institute of Clinical Pharmacology, Goethe University Frankfurt, Frankfurt, Germany. 5. Research Unit of Molecular Endocrinology and Metabolism, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, Germany. 6. Biotechnology Center Dresden, Technical University of Dresden, Dresden, Germany. 7. Research Unit of Molecular Endocrinology and Metabolism, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany. 8. 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. 9. Center of Allergy and Environment, Technical University of Munich and Helmholtz Zentrum München, Munich, Germany. Electronic address: Julia.esser-von-bieren@tum.de.
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.
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.
Authors: Constanze A Jakwerth; Jose Ordovas-Montanes; Simon Blank; Carsten B Schmidt-Weber; Ulrich M Zissler Journal: Cells Date: 2022-04-20 Impact factor: 7.666
Authors: Sina Bohnacker; Franziska Hartung; Fiona Henkel; Alessandro Quaranta; Johan Kolmert; Alina Priller; Minhaz Ud-Dean; Johanna Giglberger; Luisa M Kugler; Lisa Pechtold; Sarah Yazici; Antonie Lechner; Johanna Erber; Ulrike Protzer; Paul Lingor; Percy Knolle; Adam M Chaker; Carsten B Schmidt-Weber; Craig E Wheelock; Julia Esser-von Bieren Journal: Mucosal Immunol Date: 2022-03-15 Impact factor: 8.701
Authors: Gail M Gauvreau; Beth E Davis; Guy Scadding; Louis-Philippe Boulet; Leif Bjermer; Adam Chaker; Donald W Cockcroft; Barbro Dahlén; Wyste Fokkens; Peter Hellings; Nikolaos Lazarinis; Paul M O'Byrne; Ellen Tufvesson; Santiago Quirce; Maurits Van Maaren; Frans H de Jongh; Zuzana Diamant Journal: Eur Respir J Date: 2022-08-25 Impact factor: 33.795