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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:144

Article

Steelant, Brecht^1,3  Wawrzyniak, Paulina³  Martens, Katleen¹  Jonckheere, Anne-Charlotte¹  Pugin, Benoit¹  Schrijvers, Rik¹  Bullens, Dominique M.^1,4  Vanoirbeek, Jeroen A.²  Krawczyk, Krzysztof^3,6  Dreher, Anita³  Akdis, Cezmi A.³  Hellings, Peter W.^1,5,7 

[1] Katholieke Univ Leuven, Dept Microbiol Immunol & Transplantat, Allergy & Clin Immunol Res Grp, Leuven, Belgium

[2] Katholieke Univ Leuven, Lab Environm & Hlth, Dept Publ Hlth & Primary Care, Leuven, Belgium

[3] Univ Zurich, Swiss Inst Allergy & Asthma Res SIAF, Davos, Switzerland

[4] Univ Hosp Leuven, Clin Dept Pediat, Leuven, Belgium

[5] Univ Hosp Leuven, Clin Dept Otorhinolaryngol Head & Neck Surg, Leuven, Belgium

[6] Univ Lodz, Dept Immunol & Infect Biol, Fac Biol & Environm Protect, Lodz, Poland

[7] Univ Amsterdam, Acad Med Ctr, Dept Otorhinolaryngol, Amsterdam, Netherlands

关键词: Allergic rhinitis;    tight junctions;    primary nasal epithelial cells;    epigenetic changes;    histone deacetylase;   

DOI  :  10.1016/j.jaci.2019.04.027

来源: Elsevier

【 摘 要 】

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-clextran (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.

【 授权许可】

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