IL-4Rα Blockade Reduces Levels of IL-6 Family Cytokines Including Oncostatin M (OSM) and IL-6 in Nasal Fluid of Patients with Aspirin Exacerbated Respiratory Disease (AERD) and Nasal Polyps

IL-4Rα blockade reduces nasal polyp burden and upper respiratory symptoms in patients with AERD. The exact cellular and molecular mechanisms of therapeutic benefit are unknown. Olink® proteomics platform was used to compare nasal fluid cytokine/chemokine levels from healthy controls (n=10) and AERD patients (n=22) at baseline and again at 1 and 3 months of dupilumab. Single-cell RNA sequencing of nasal polyp tissue was used to identify the primary cellular sources of those cytokines. Cultured human cord blood-derived mast cells (CBMCs), peripheral blood-derived monocytes, and human nasal fibroblasts were stimulated with and without IL-4, IL-13, and OSM to determine their effects on OSM and IL-6 production. There were significantly higher baseline levels of multiple cytokines, particularly the IL-6 family cytokines, OSM and IL-6, in nasal fluid of AERD patients versus controls. Dupilumab significantly reduced the nasal levels of IL-6 and OSM in AERD patients. Nasal polyp mast cells and monocytes expressed high levels of OSM transcripts. IL-4 stimulation of CBMCs and cultured monocytes increased their OSM production, while IL-13 and OSM stimulation of fibroblasts increased their IL-6 production. AERD patients have high nasal fluid levels of the innate inflammatory cytokines OSM and IL-6, which are known to have many downstream effects including inducing respiratory epithelial cell disruption. The dupilumab-induced decrease in nasal OSM and IL-6, which is likely due to direct effects of IL-4Rα blockade on tissue mast cells and monocytes, and both indirect and direct effects on nasal fibroblasts, may be partially responsible for the therapeutic benefit of dupilumab.