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

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

Belinostat resolves skin barrier defects in atopic dermatitis by targeting the dysregulated miR-335:SOX6 axis

“…33,34 Recently, it was demonstrated that blocking HDAC activity by using JNJ-26481585, a broad-spectrum HDACI, is crucial to restore nasal mucosal function by promoting tight junction expression. 54 This led us to hypothesize that HDACIs may be effective in treating AD, partly by upregulating miR-335 expression, which can induce differentiation-associated transcriptional signature and restore barrier function. Our screening assay resulted in the identification of belinostat as a highly effective HDACI that can potently restore both epidermal miR-335 and downstream keratinocyte differentiation-related genes.…”

The influence of corticosteroids and Azelastine on epithelial cell integrity in chronic rhinosinusitis with polyps

“…By blocking HDAC activity it was possible to restore barrier integrity on different levels: The TER, immunostaining of TJ proteins and measurement of mRNA levels of the proteins showed a significant increase. These findings are important to understand the multilevel and multiparametric pathogenesis of barrier dysfunction as well as the importance of the cell layer integrity for a healthy subject (27) . Interestingly, HDAC activity can be inhibited by sodium butyrate which is an end product of the gut microbiome (28) .…”

RAGE mediates airway inflammation via the HDAC1 pathway in a toluene diisocyanate-induced murine asthma model

“…Another study demonstrated that treatment with HDAC inhibitors suppressed airway inflammation in a murine model of chronic allergic airway disease (Royce et al 2012). Blocking HDAC activity may be a novel target for epithelial barrier defects in patients with asthma and allergic rhinitis (Wawrzyniak et al 2017;Steelant et al 2019). As such, the results of the current study also suggest that blocking HDAC activity may be a novel therapeutic intervention for asthmatic patients.…”