Publication date: Available online 11 May 2019
Source: Journal of Allergy and Clinical Immunology
Author(s): 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
Abstract
Graphical abstract
Background
A defective epithelial barrier is found in 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 if HDAC activity has been altered in AR and a mouse model of house dust mite (HDM)-induced allergic asthma, and if it contributed to epithelial barrier dysfunction.
Methods
Primary nasal epithelial cells of controls and AR patients were cultured at air-liquid interface (ALI) to study trans-epithelial electrical resistance, paracellular flux of FITC-dextran 4kDa, together with mRNA expression and immunofluorescence staining of tight junctions. ALI 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 higher in nasal epithelial cells of AR patients 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. To demonstrate the in vivo role of HDACs, HDM-sensitized mice were treated with JNJ-26481585. Treated mice did not develop 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 airway diseases.
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