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

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

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: Frequent exacerbations of allergic asthma lead to airway remodeling and a decrease 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 using quantitative RT-PCR. We developed a model of aeroallergen-induced experimental asthma using repetitive cat dander extract exposure. We measured airway inflammation using immunofluorescence, leukocyte recruitment, and quantitative RT-PCR. Airway remodeling was measured by using histology, collagen content, myofibroblast numbers, and selected reaction monitoring. Inducible nuclear factor κB (NF-κB)–BRD4 interaction was measured by using a proximity ligation assay in situ. Results: Enhanced mesenchymal signatures are observed in bronchial biopsy specimens from patients with allergic asthma. Cat dander induces innate inflammation through NF-κB signaling, followed by production of a profibrogenic mesenchymal transition in primary human small airway epithelial cells. The IκB kinase–NF-κB signaling pathway is required for mucosal inflammation-coupled airway remodeling and myofibroblast expansion in the mouse model of aeroallergen exposure. Cat dander induces NF-κB/RelA to complex with and activate BRD4, resulting in modifying the chromatin environment of inflammatory and fibrogenic genes through its atypical histone acetyltransferase activity. A novel small-molecule BRD4 inhibitor (ZL0454) disrupts BRD4 binding to the NF-κB–RNA polymerase II complex and inhibits its histone acetyltransferase activity. ZL0454 prevents epithelial mesenchymal transition, myofibroblast expansion, IgE sensitization, and fibrosis in airways of naive mice exposed to cat dander. Conclusions: NF-κB–inducible BRD4 activity mediates cat dander–induced inflammation and remodeling. Therapeutic modulation of the NF-κB–BRD4 pathway affects allergen-induced inflammation, epithelial cell-state changes, extracellular matrix production, and expansion of the subepithelial myofibroblast population.

Original languageEnglish (US)
JournalJournal of Allergy and Clinical Immunology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Dander
Cats
Inflammation
Myofibroblasts
Airway Remodeling
Asthma
Proteins
Histone Acetyltransferases
Epithelial Cells
Polymerase Chain Reaction
Epithelial-Mesenchymal Transition
Allergens
Immunoglobulin E
Chromatin
Fluorescent Antibody Technique
Extracellular Matrix
Ligation
Histology
Leukocytes
Fibrosis

Keywords

  • aeroallergen
  • airway remodeling
  • Bromodomain-containing protein 4
  • epigenetics
  • histone acetyltransferase activity
  • myofibroblast
  • nuclear factor κB

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Mucosal bromodomain-containing protein 4 mediates aeroallergen-induced inflammation and remodeling. / Tian, Bing; Hosoki, Koa; Liu, Zhiqing; Yang, Jun; Zhao, Yingxin; Sun, Hong; Zhou, Jia; Rytting, Erik; Kaphalia, Lata; Calhoun, William; Sur, Sanjiv; Brasier, Allan R.

In: Journal of Allergy and Clinical Immunology, 01.01.2018.

Research output: Contribution to journalArticle

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abstract = "Background: Frequent exacerbations of allergic asthma lead to airway remodeling and a decrease 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 using quantitative RT-PCR. We developed a model of aeroallergen-induced experimental asthma using repetitive cat dander extract exposure. We measured airway inflammation using immunofluorescence, leukocyte recruitment, and quantitative RT-PCR. Airway remodeling was measured by using histology, collagen content, myofibroblast numbers, and selected reaction monitoring. Inducible nuclear factor κB (NF-κB)–BRD4 interaction was measured by using a proximity ligation assay in situ. Results: Enhanced mesenchymal signatures are observed in bronchial biopsy specimens from patients with allergic asthma. Cat dander induces innate inflammation through NF-κB signaling, followed by production of a profibrogenic mesenchymal transition in primary human small airway epithelial cells. The IκB kinase–NF-κB signaling pathway is required for mucosal inflammation-coupled airway remodeling and myofibroblast expansion in the mouse model of aeroallergen exposure. Cat dander induces NF-κB/RelA to complex with and activate BRD4, resulting in modifying the chromatin environment of inflammatory and fibrogenic genes through its atypical histone acetyltransferase activity. A novel small-molecule BRD4 inhibitor (ZL0454) disrupts BRD4 binding to the NF-κB–RNA polymerase II complex and inhibits its histone acetyltransferase activity. ZL0454 prevents epithelial mesenchymal transition, myofibroblast expansion, IgE sensitization, and fibrosis in airways of naive mice exposed to cat dander. Conclusions: NF-κB–inducible BRD4 activity mediates cat dander–induced inflammation and remodeling. Therapeutic modulation of the NF-κB–BRD4 pathway affects allergen-induced inflammation, epithelial cell-state changes, extracellular matrix production, and expansion of the subepithelial myofibroblast population.",
keywords = "aeroallergen, airway remodeling, Bromodomain-containing protein 4, epigenetics, histone acetyltransferase activity, myofibroblast, nuclear factor κB",
author = "Bing Tian and Koa Hosoki and Zhiqing Liu and Jun Yang and Yingxin Zhao and Hong Sun and Jia Zhou and Erik Rytting and Lata Kaphalia and William Calhoun and Sanjiv Sur and Brasier, {Allan R.}",
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AU - Tian, Bing

AU - Hosoki, Koa

AU - Liu, Zhiqing

AU - Yang, Jun

AU - Zhao, Yingxin

AU - Sun, Hong

AU - Zhou, Jia

AU - Rytting, Erik

AU - Kaphalia, Lata

AU - Calhoun, William

AU - Sur, Sanjiv

AU - Brasier, Allan R.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background: Frequent exacerbations of allergic asthma lead to airway remodeling and a decrease 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 using quantitative RT-PCR. We developed a model of aeroallergen-induced experimental asthma using repetitive cat dander extract exposure. We measured airway inflammation using immunofluorescence, leukocyte recruitment, and quantitative RT-PCR. Airway remodeling was measured by using histology, collagen content, myofibroblast numbers, and selected reaction monitoring. Inducible nuclear factor κB (NF-κB)–BRD4 interaction was measured by using a proximity ligation assay in situ. Results: Enhanced mesenchymal signatures are observed in bronchial biopsy specimens from patients with allergic asthma. Cat dander induces innate inflammation through NF-κB signaling, followed by production of a profibrogenic mesenchymal transition in primary human small airway epithelial cells. The IκB kinase–NF-κB signaling pathway is required for mucosal inflammation-coupled airway remodeling and myofibroblast expansion in the mouse model of aeroallergen exposure. Cat dander induces NF-κB/RelA to complex with and activate BRD4, resulting in modifying the chromatin environment of inflammatory and fibrogenic genes through its atypical histone acetyltransferase activity. A novel small-molecule BRD4 inhibitor (ZL0454) disrupts BRD4 binding to the NF-κB–RNA polymerase II complex and inhibits its histone acetyltransferase activity. ZL0454 prevents epithelial mesenchymal transition, myofibroblast expansion, IgE sensitization, and fibrosis in airways of naive mice exposed to cat dander. Conclusions: NF-κB–inducible BRD4 activity mediates cat dander–induced inflammation and remodeling. Therapeutic modulation of the NF-κB–BRD4 pathway affects allergen-induced inflammation, epithelial cell-state changes, extracellular matrix production, and expansion of the subepithelial myofibroblast population.

AB - Background: Frequent exacerbations of allergic asthma lead to airway remodeling and a decrease 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 using quantitative RT-PCR. We developed a model of aeroallergen-induced experimental asthma using repetitive cat dander extract exposure. We measured airway inflammation using immunofluorescence, leukocyte recruitment, and quantitative RT-PCR. Airway remodeling was measured by using histology, collagen content, myofibroblast numbers, and selected reaction monitoring. Inducible nuclear factor κB (NF-κB)–BRD4 interaction was measured by using a proximity ligation assay in situ. Results: Enhanced mesenchymal signatures are observed in bronchial biopsy specimens from patients with allergic asthma. Cat dander induces innate inflammation through NF-κB signaling, followed by production of a profibrogenic mesenchymal transition in primary human small airway epithelial cells. The IκB kinase–NF-κB signaling pathway is required for mucosal inflammation-coupled airway remodeling and myofibroblast expansion in the mouse model of aeroallergen exposure. Cat dander induces NF-κB/RelA to complex with and activate BRD4, resulting in modifying the chromatin environment of inflammatory and fibrogenic genes through its atypical histone acetyltransferase activity. A novel small-molecule BRD4 inhibitor (ZL0454) disrupts BRD4 binding to the NF-κB–RNA polymerase II complex and inhibits its histone acetyltransferase activity. ZL0454 prevents epithelial mesenchymal transition, myofibroblast expansion, IgE sensitization, and fibrosis in airways of naive mice exposed to cat dander. Conclusions: NF-κB–inducible BRD4 activity mediates cat dander–induced inflammation and remodeling. Therapeutic modulation of the NF-κB–BRD4 pathway affects allergen-induced inflammation, epithelial cell-state changes, extracellular matrix production, and expansion of the subepithelial myofibroblast population.

KW - aeroallergen

KW - airway remodeling

KW - Bromodomain-containing protein 4

KW - epigenetics

KW - histone acetyltransferase activity

KW - myofibroblast

KW - nuclear factor κB

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