{Reference Type}: Journal Article
{Title}: IL-4Rα signaling promotes barrier-altering oncostatin M and IL-6 production in aspirin-exacerbated respiratory disease.
{Author}: Chen CC;Buchheit KM;Lee PY;Brodeur KE;Sohail A;Cho L;Baloh CH;Balestrieri B;Derakhshan T;Feng C;Boyce JA;Dwyer DF;Laidlaw TM;
{Journal}: J Allergy Clin Immunol
{Volume}: 154
{Issue}: 2
{Year}: 2024 Aug 3
{Factor}: 14.29
{DOI}: 10.1016/j.jaci.2024.04.020
{Abstract}: <B>BACKGROUND: </B>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.<BR><B>OBJECTIVE: </B>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.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.