Blocking histone deacetylase activity as a novel target for epithelial barrier defects in patients with allergic rhinitis

Brecht Steelant; Paulina Wawrzyniak; Katleen Martens; Anne-Charlotte Jonckheere; Benoit Pugin; Rik Schrijvers; Dominique M Bullens; Jeroen A Vanoirbeek; Krzysztof Krawczyk; Anita Dreher; Cezmi A Akdis; Peter W Hellings

doi:10.1016/j.jaci.2019.04.027

Blocking histone deacetylase activity as a novel target for epithelial barrier defects in patients with allergic rhinitis

J Allergy Clin Immunol. 2019 Nov;144(5):1242-1253.e7. doi: 10.1016/j.jaci.2019.04.027. Epub 2019 May 11.

Affiliations

¹ Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium; Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
² Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
³ Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium.
⁴ Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium; Clinical Department of Pediatrics, Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium.
⁵ Department of Public Health and Primary Care, Laboratory of Environment and Health, KU Leuven, Leuven, Belgium.
⁶ Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland.
⁷ Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium; Clinical Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Otorhinolaryngology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: Peter.hellings@kuleuven.be.

PMID: 31082457
DOI: 10.1016/j.jaci.2019.04.027

Abstract

Background: A defective epithelial barrier is found in patients with allergic rhinitis (AR) and asthma; however, the underlying mechanisms remain poorly understood. Histone deacetylase (HDAC) activity has been identified as a crucial driver of allergic inflammation and tight junction dysfunction.

Objective: We investigated whether HDAC activity has been altered in patients with AR and in a mouse model of house dust mite (HDM)-induced allergic asthma and whether it contributed to epithelial barrier dysfunction.

Methods: Primary nasal epithelial cells of control subjects and patients with AR were cultured at the air-liquid interface to study transepithelial electrical resistance and paracellular flux of fluorescein isothiocyanate-dextran (4 kDa) together with mRNA expression and immunofluorescence staining of tight junctions. Air-liquid interface cultures were stimulated with different concentrations of JNJ-26481585, a broad-spectrum HDAC inhibitor. In vivo the effect of JNJ-26481585 on mucosal permeability and tight junction function was evaluated in a mouse model of HDM-induced allergic airway inflammation.

Results: General HDAC activity was greater in nasal epithelial cells of patients with AR and correlated inversely with epithelial integrity. Treatment of nasal epithelial cells with JNJ-26481585 restored epithelial integrity by promoting tight junction expression and protein reorganization. HDM-sensitized mice were treated with JNJ-26481585 to demonstrate the in vivo role of HDACs. Treated mice did not have allergic airway inflammation and had no bronchial hyperreactivity. Moreover, JNJ-26481585 treatment restored nasal mucosal function by promoting tight junction expression.

Conclusion: Our findings identify increased HDAC activity as a potential tissue-injury mechanism responsible for dysregulated epithelial cell repair, leading to defective epithelial barriers in AR. Blocking HDAC activity is a promising novel target for therapeutic intervention in patients with airway diseases.

Keywords: Allergic rhinitis; epigenetic changes; histone deacetylase; primary nasal epithelial cells; tight junctions.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Dermatophagoides / immunology
Asthma / metabolism*
Cells, Cultured
Disease Models, Animal
Histone Deacetylase Inhibitors / pharmacology
Histone Deacetylases / metabolism*
Humans
Hydroxamic Acids / pharmacology
Male
Mice
Mice, Inbred C57BL
Nasal Mucosa / metabolism*
Nasal Mucosa / pathology
Rhinitis, Allergic / metabolism*
Tight Junctions / metabolism*
Tight Junctions / pathology

Substances

Antigens, Dermatophagoides
Histone Deacetylase Inhibitors
Hydroxamic Acids
quisinostat
Histone Deacetylases