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Hartung, F. ; Haimerl, P. ; Schindela, S. ; Mussack, V.* ; Kirchner, B.* ; Henkel, F. ; Bernhardt, U. ; Zissler, U.M. ; Santarella-Mellwig, R.* ; Pfaffl, M.* ; Schmidt-Weber, C.B. ; Chaker, A. ; Esser-von Bieren, J.

Extracellular vesicle miRNAs drive aberrant macrophage responses in NSAID-exacerbated respiratory disease.

Allergy, DOI: 10.1111/all.16117 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
BACKGROUND: Extracellular vesicles (EVs) have been implicated in the pathogenesis of asthma, however, how EVs contribute to immune dysfunction and type 2 airway inflammation remains incompletely understood. We aimed to elucidate roles of airway EVs and their miRNA cargo in the pathogenesis of NSAID-exacerbated respiratory disease (N-ERD), a severe type 2 inflammatory condition. METHODS: EVs were isolated from induced sputum or supernatants of cultured nasal polyp or turbinate tissues of N-ERD patients or healthy controls by size-exclusion chromatography and characterized by particle tracking, electron microscopy and miRNA sequencing. Functional effects of EV miRNAs on gene expression and mediator release by human macrophages or normal human bronchial epithelial cells (NHBEs) were studied by RNA sequencing, LC-MS/MS and multiplex cytokine assays. RESULTS: EVs were highly abundant in secretions from the upper and lower airways of N-ERD patients. N-ERD airway EVs displayed profoundly altered immunostimulatory capacities and miRNA profiles compared to airway EVs of healthy individuals. Airway EVs of N-ERD patients, but not of healthy individuals induced inflammatory cytokine (GM-CSF and IL-8) production by NHBEs. In macrophages, N-ERD airway EVs exhibited an impaired potential to induce cytokine and prostanoid production, while enhancing M2 macrophage activation. Let-7 family miRNAs were highly enriched in sputum EVs from N-ERD patients and mimicked suppressive effects of N-ERD EVs on macrophage activation. CONCLUSION: Aberrant airway EV miRNA profiles may contribute to immune dysfunction and chronic type 2 inflammation in N-ERD. Let-7 family miRNAs represent targets for correcting aberrant macrophage activation and mediator responses in N-ERD.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Crswnp ; Asthma ; Extracellular Vesicles ; Macrophages ; Type 2 Immunity; Lavage Fluid Exosomes; Dendritic Cells; Airway; Micrornas; Aspirin; Expression; Inhibition; Uncovers; Lung; Rnas
ISSN (print) / ISBN 0105-4538
e-ISSN 1398-9995
Journal Allergy
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute for Allergy Research (IAF)
Grants Helmholtz Initiative and Networking
Deutsche Forschungsgemeinschaft
Else Kroner-Fresenius-Stiftung