Inflammatory macrophage memory in NSAID-exacerbated respiratory disease.

Abstract Background NSAID-exacerbated respiratory disease (N-ERD) is a chronic inflammatory condition, which is driven by an aberrant arachidonic acid (AA) metabolism. Macrophages are major producers of AA metabolites and subject to metabolic reprogramming, but they have been neglected in N-ERD. Objective We sought to elucidate a potential metabolic and epigenetic macrophage reprogramming in N-ERD. Methods Transcriptional, metabolic and lipid mediator profiles in macrophages from N-ERD patients and healthy controls were assessed by RNA sequencing, Seahorse assays and LC-MS/MS. Metabolites in nasal lining fluid, sputum and plasma from N-ERD patients (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 We show 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 pro-inflammatory activation. Differentially methylated regions (DMRs) 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 N-ERD patients. Upon inflammatory challenge, N-ERD macrophages produced increased levels of acylcarnitines, pro-inflammatory AA metabolites, cytokines and chemokines as compared to healthy macrophages. Conclusion Together, our findings decipher a pro-inflammatory metabolic and epigenetic reprogramming of macrophages in N-ERD.