Mucosal bromodomain-containing protein 4 mediates aeroallergen-induced inflammation and remodeling

Background Frequent exacerbations of allergic asthma lead to airway remodeling and a decrease in pulmonary function, producing morbidity. Cat danderis an aeroallergenassociated with asthma risk. Objective We sought to elucidate the mechanism of cat dander–induced inflammation-remodeling. Methods We identified remodeling in mucosal samples from allergic asthma by using quantitative RT-PCR. We developed a model of aeroallergen-induced experimental asthma using repetitive cat danderextract exposure. We measured airway inflammation using immunofluorescence, leukocyte recruitment, and quantitative RT-PCR. Airway remodeling was measured by using histology, collagen content, myofibroblastnumbers, and selected reaction monitoring. Inducible nuclear factor κB ( NF-κB)– BRD4interaction was measured by using a proximity ligation assayin situ . Results Enhanced mesenchymal signatures are observed in bronchial biopsy specimens from patients with allergic asthma. Cat danderinduces innate inflammation through NF-κBsignaling, followed by production of a profibrogenic mesenchymal transition in primary human small airway epithelial cells. The IκB kinase– NF-κBsignaling pathway is required for mucosal inflammation-coupled airway remodeling and myofibroblastexpansion in the mouse model of aeroallergenexposure. Cat danderinduces NF-κB/RelA to complex with and activate BRD4, resulting in modifying the chromatin environment of inflammatory and fibrogenic genes through its atypical histone acetyltransferaseactivity. A novel small-molecule BRD4inhibitor (ZL0454) disrupts BRD4binding to the NF-κB–RNA polymerase II complex and inhibits its histone acetyltransferaseactivity. ZL0454 prevents epithelial mesenchymal transition, myofibroblastexpansion, IgE sensitization, and fibrosis in airways of naive mice exposed to cat dander. Conclusions NF-κB–inducible BRD4activity mediates cat dander–induced inflammation and remodeling. Therapeutic modulation of the NF-κB– BRD4pathway affects allergen-induced inflammation, epithelial cell-state changes, extracellular matrix production, and expansion of the subepithelial myofibroblastpopulation.