The Journal of allergy and clinical immunology · 2020
Inflammatory macrophage memory in nonsteroidal anti-inflammatory drug-exacerbated respiratory disease.
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Haimerl Pascal, Bernhardt Ulrike, Schindela Sonja, Henkel Fiona D R, Lechner Antonie, Zissler Ulrich M, Pastor Xavier, Thomas Dominique, Cecil Alexander, Ge Yan, Haid Mark, Prehn Cornelia, Tokarz Janina, Heinig Matthias, Adamski Jerzy, Schmidt-Weber Carsten B, Chaker Adam M, Esser-von Bieren Julia
Аннотация
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.
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.