Mucosal Bromodomain-Containing Protein 4 (BRD4) Mediates Aeroallergen-induced Inflammation and Remodeling

Publication date: Available online 13 October 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Bing Tian, Koa Hosoki, Zhiqing Liu, Jun Yang, Yingxin Zhao, Hong Sun, Jia Zhou, Erik Rytting, Lata Kaphalia, William J. Calhoun, Sanjiv Sur, Allan R. Brasier

Abstract

Background

Frequent exacerbations of allergic asthma leads to airway remodeling and a decline in pulmonary function, producing morbidity. Cat dander is an aeroallergen associated 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 Q-RT-PCR. We developed a model of aeroallergen-induced experimental asthma by repetitive cat dander extract exposure. We measured airway inflammation using immunofluorescence, leukocyte recruitment and Q-RT-PCR. Airway remodeling was measured using histology, collagen content, myofibroblast numbers and selected reaction monitoring. Inducible NFκB-BRD4 interaction was measured by proximity ligation assay in situ.

Results

Enhanced mesenchymal signatures are observed in bronchial biopsies from patients with allergic asthma. Cat dander induces innate inflammation via NFκB signaling, followed by producing a pro-fibrogenic, mesenchymal transition (EMT) in primary human small airway epithelial cells. The IκB kinase (IKK)-NFκB signaling pathway is required for mucosal inflammation-coupled airway remodeling and myofibroblast expansion in the mouse model of aeroallergen exposure. Cat dander induces NFκB/RelA to complex with and activate BRD4, resulting in modifying the chromatin environment of inflammatory and fibrogenic genes through its atypical histone acetyltransferase (HAT) activity. A novel, small-molecule BRD4 inhibitor (ZL0454) disrupts BRD4 binding to the NFκB-RNA Pol II complex and inhibits its HAT activity. ZL0454 prevents EMT, myofibroblast expansion, IgE sensitization, and fibrosis in airways of naïve mice exposed to cat dander.

Conclusions

NFκB-inducible BRD4 activity mediates cat dander-induced inflammation and remodeling. Therapeutic modulation of the NFκB-BRD4 pathway affects allergen-induced inflammation, epithelial cell-state changes, ECM production and expansion of the subepithelial myofibroblast population.

Graphical abstract

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