Regulation of bronchial epithelial barrier integrity by type 2 cytokines and histone deacetylases in asthmatic patients Paulina Wawrzyniak, MSc, Marcin.

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Presentation transcript:

Regulation of bronchial epithelial barrier integrity by type 2 cytokines and histone deacetylases in asthmatic patients Paulina Wawrzyniak, MSc, Marcin Wawrzyniak, PhD, Kerstin Wanke, PhD, Milena Sokolowska, MD, PhD, Kreso Bendelja, PhD, Beate Rückert, Sci Tec, Anna Globinska, MSc, Bogdan Jakiela, MD, PhD, Jeannette I. Kast, MSc, Marco Idzko, MD, Mübeccel Akdis, MD, PhD, Marek Sanak, MD, PhD, Cezmi A. Akdis, MD Journal of Allergy and Clinical Immunology Volume 139, Issue 1, Pages 93-103 (January 2017) DOI: 10.1016/j.jaci.2016.03.050 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Barrier defect in ALI cultures of HBECs from asthmatic patients and their response to TH2 cells. A, TER during development of ALI cultures from days 3 to 7 in HBECs from control subjects and asthmatic patients. B, TER from HBECs after differentiation on day 21. C, TER in response to TH2 cells in ALI cultures of control subjects and asthmatic patients. D, Paracellular flux of 4-kDa FITC-dextran in response to TH2 cells in ALI cultures from control subjects and asthmatic patients. E, Representative immunofluorescence staining of occludin and ZO-1 in ALI cocultured with TH2 cells (5 × 105 cells, 48 hours) in HBECs from control subjects and ALI cultures of asthmatic patients. Arrows point out stratification of TJs. Data are presented as means ± SDs. *P < .05, **P < .01, and ***P < .001, Wilcoxon rank sum test. N = 6 per group in duplicates. u.s., Unstimulated. Journal of Allergy and Clinical Immunology 2017 139, 93-103DOI: (10.1016/j.jaci.2016.03.050) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Decreased epithelial barrier by IL-4 and IL-13 in ALI cultures. A, TER from IL-4 and IL-13 (50 ng/mL)–stimulated HBECs from control subjects and asthmatic patients in ALI cultures. B, Paracellular flux of 4-kDa FITC-dextran after stimulation with IL-4 and IL-13 (50 ng/mL) in HBECs from control subjects and asthmatic patients. C, Representative immunofluorescence staining of occludin and ZO-1 in ALI cultures stimulated with IL-4 and IL-13 (50 ng/mL, 48 hours) in control and asthmatic donors. Arrows point out stratification of TJs. Data are presented as means ± SDs. *P < .05, **P < .01, and ***P < .001, Wilcoxon rank sum test. N = 6 per group in duplicates. u.s., Unstimulated. Journal of Allergy and Clinical Immunology 2017 139, 93-103DOI: (10.1016/j.jaci.2016.03.050) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Increased expression of HDACs by IL-4 and IL-13. A, Expression of 11 members of the HDAC family of ALI cultures in HBECs from control subjects and asthmatic patients with IL-4 (50 ng/mL) and IL-13 (50 ng/mL) for 48 hours. Measurement was performed with the TaqMan Micro Fluidic Card system. Data represent means ± SDs. *P < .05, **P < .01, ***P < .001, and ****P < .0001, Student t test. N = 5 per group. u.s., Unstimulated. B, Representative Western blots of HDACs 1, 2, and 7 in HBECs from control subjects and asthmatic patients after stimulation with IL-4 and IL-13 (n = 3 per group). Journal of Allergy and Clinical Immunology 2017 139, 93-103DOI: (10.1016/j.jaci.2016.03.050) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 HDAC inhibition increased TJ expression in epithelial cells. A, HDAC activity in control and asthmatic donors (n = 4 per group). B, TER in ALI cultures of HBECs from control subjects and asthmatic patients treated with 10 nmol/L HDAC inhibitor (JNJ-26481585). C, Fluorescence intensity for occludin and ZO-1 measured from immunofluorescence staining of HBECs from asthmatic patients treated with indicated doses of JNJ-26481585 for 72 hours. D, Representative immunofluorescence staining of occludin and ZO-1 in HBECs from asthmatic patients after treatment with HDAC inhibitor (Fig 4, C and D, n = 3 per group). E, mRNA expression of occludin, ZO-1, claudin-7, and claudin-1 in ALI cultures of HBECs from control and asthmatic donors after HDAC inhibition for 72 hours. Data represent means ± SDs. *P < .05, **P < .01, and ***P < .001, 2-way ANOVA. N = 8 per group. u.t., Untreated. Journal of Allergy and Clinical Immunology 2017 139, 93-103DOI: (10.1016/j.jaci.2016.03.050) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 HDAC inhibition protects bronchial epithelial cell barrier damage caused by IL-4 and IL-13. A, TER HBECs from control subjects and asthmatic patients pretreated with 10 nmol/L HDAC inhibitor (JNJ-26481585). After 72 hours of treatment, HDAC inhibitor was washed away, and all epithelial cells were stimulated with IL-4 (50 ng/mL) and IL-13 (50 ng/mL) for 72 hours. TER measurement was performed. Data represent means ± SDs. ***P < .001, 2-way ANOVA test. N = 3 per group. B, TER measurement of bronchial epithelial cells from control and asthmatic donors stimulated with IL-4 (10 ng/mL) and IL-13 (10 ng/mL) and with the HDAC inhibitor JNJ-26481585 (100 nmol/L) for 72 hours (n = 3). Data are presented as means ± SDs. *P < .05 and **P < .01, unpaired t test. N = 3 per group. u.s., Unstimulated. C, TER measurement of bronchial epithelial cells from control and asthmatic donors stimulated with IL-4 (10 ng/mL) and IL-13 (10 ng/mL) and together with the HDAC inhibitor JNJ-26481585 (100 nmol/L) for 72 hours (n = 3). Data are presented as means ± SDs. *P < .05 and **P < .01, unpaired t test. N = 3 per group. u.s., Unstimulated. Journal of Allergy and Clinical Immunology 2017 139, 93-103DOI: (10.1016/j.jaci.2016.03.050) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions