Regulation of bronchial epithelial barrier integrity by type 2 cytokines and histone deacetylases in asthmatic patients

Paulina Wawrzyniak; Marcin Wawrzyniak; Kerstin Wanke; Milena Sokolowska; Kreso Bendelja; Beate Rückert; Anna Globinska; Bogdan Jakiela; Jeannette I Kast; Marco Idzko; Mübeccel Akdis; Marek Sanak; Cezmi A Akdis

doi:10.1016/j.jaci.2016.03.050

Regulation of bronchial epithelial barrier integrity by type 2 cytokines and histone deacetylases in asthmatic patients

J Allergy Clin Immunol. 2017 Jan;139(1):93-103. doi: 10.1016/j.jaci.2016.03.050. Epub 2016 May 11.

Affiliations

¹ Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland, Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.
² Institute of Immunology, Zagreb, Croatia.
³ Department of Medicine, Jagiellonian University Medical College, Krakow, Poland.
⁴ Department of Pneumology, University Hospital Freiburg, Freiburg, Germany.
⁵ Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland, Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland. Electronic address: akdiasac@siaf.uzh.ch.

PMID: 27312821
DOI: 10.1016/j.jaci.2016.03.050

Abstract

Background: Tight junctions (TJs) form a barrier on the apical side of neighboring epithelial cells in the bronchial mucosa. Changes in their integrity might play a role in asthma pathogenesis by enabling the paracellular influx of allergens, toxins, and microbes to the submucosal tissue.

Objective: The regulation of bronchial epithelial TJs by T_H2 cells and their cytokines and their involvement in epigenetic regulation of barrier function were investigated.

Methods: The expression, regulation, and function of TJs were determined in air-liquid interface (ALI) cultures of control and asthmatic primary human bronchial epithelial cells (HBECs) by means of analysis of transepithelial electrical resistance, paracellular flux, mRNA expression, Western blotting, and immunofluorescence staining.

Results: HBECs from asthmatic patients showed a significantly low TJ integrity in ALI cultures compared with HBECs from healthy subjects. T_H2 cell numbers and levels of their cytokines, IL-4 and IL-13, decreased barrier integrity in ALI cultures of HBECs from control subjects but not in HBECs from asthmatic patients. They induced a physical separation of the TJs of adjacent cells in immunofluorescence staining of the TJ molecules occludin and zonula occludens-1. We observed that expression of histone deacetylases (HDACs) 1 and 9, and Silent information regulator genes (sirtuins [SIRTs]) 6 and 7 were significantly high in HBECs from asthmatic patients. IL-4 and IL-13 significantly increased the expression of HDACs and SIRTs. The role of HDAC activation on epithelial barrier leakiness was confirmed by HDAC inhibition, which improved barrier integrity through increased synthesis of TJ molecules in epithelium from asthmatic patients to the level seen in HBECs from control subjects.

Conclusion: Our data demonstrate that barrier leakiness in asthmatic patients is induced by T_H2 cells, IL-4, and IL-13 and HDAC activity. The inhibition of endogenous HDAC activity reconstitutes defective barrier by increasing TJ expression.

Keywords: Asthma; IL-13; IL-4; T(H)2 cells; bronchial epithelial cells; epigenetic; histone deacetylase; tight junctions.

Publication types

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

MeSH terms

Adult
Asthma / metabolism*
Bronchi / cytology
Cytokines / metabolism*
Epithelial Cells / metabolism*
Female
Histone Deacetylases / genetics
Histone Deacetylases / metabolism
Humans
Male
Middle Aged
RNA, Messenger / metabolism
Th2 Cells / metabolism
Tight Junctions / metabolism*

Substances

Cytokines
RNA, Messenger
Histone Deacetylases