IL-4Rα signaling promotes barrier-altering oncostatin M and IL-6 production in aspirin-exacerbated respiratory disease - 04/06/24
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Graphical abstract |
Abstract |
Background |
Aspirin-exacerbated respiratory disease (AERD) is a severe disease involving dysregulated type 2 inflammation. However, the role other inflammatory pathways play in AERD is poorly understood.
Objective |
We sought to broadly define the inflammatory milieu of the upper respiratory tract in AERD and to determine the effects of IL-4Rα inhibition on mediators of nasal inflammation.
Methods |
Twenty-two AERD patients treated with dupilumab for 3 months were followed over 3 visits and compared to 10 healthy controls. Nasal fluid was assessed for 45 cytokines and chemokines using Olink Target 48. Blood neutrophils and cultured human mast cells, monocytes/macrophages, and nasal fibroblasts were assessed for response to IL-4/13 stimulation in vitro.
Results |
Of the nasal fluid cytokines measured, nearly one third were higher in AERD patients compared to healthy controls, including IL-6 and the IL-6 family–related cytokine oncostatin M (OSM), both of which correlated with nasal albumin levels, a marker of epithelial barrier dysregulation. Dupilumab significantly decreased many nasal mediators, including OSM and IL-6. IL-4 stimulation induced OSM production from mast cells and macrophages but not from neutrophils, and OSM and IL-13 stimulation induced IL-6 production from nasal fibroblasts.
Conclusion |
In addition to type 2 inflammation, innate and IL-6–related cytokines are also elevated in the respiratory tract in AERD. Both OSM and IL-6 are locally produced in nasal polyps and likely promote pathology by negatively affecting epithelial barrier function. IL-4Rα blockade, although seemingly directed at type 2 inflammation, also decreases mediators of innate inflammation and epithelial dysregulation, which may contribute to dupilumab’s therapeutic efficacy in AERD.
Le texte complet de cet article est disponible en PDF.Key words : Aspirin-exacerbated respiratory disease, AERD, interleukin 4Rα, interleukin 4, interleukin 6, interleukin 13, nasal polyp, dupilumab, oncostatin M, mast cells
Abbreviations used : AERD, CBMC, CCL, CRSsNP, CRSwNP, CSF, G-CSF/CSF3, GM-CSF/CSF2, MC, M-CSF/CSF1, MDM, MMP, NP, OSM, OSMR, scRNA-Seq, TSLP
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