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Ozone exposure induces respiratory barrier biphasic injury and inflammation controlled by IL-33  Chloé Michaudel, PhD, Claire Mackowiak, MSc, Isabelle.

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Presentation on theme: "Ozone exposure induces respiratory barrier biphasic injury and inflammation controlled by IL-33  Chloé Michaudel, PhD, Claire Mackowiak, MSc, Isabelle."— Presentation transcript:

1 Ozone exposure induces respiratory barrier biphasic injury and inflammation controlled by IL-33 
Chloé Michaudel, PhD, Claire Mackowiak, MSc, Isabelle Maillet, BSc, Louis Fauconnier, MSc, Cezmi A. Akdis, MD, Milena Sokolowska, MD, PhD, Anita Dreher, MSc, Hern-Tze Tina Tan, PhD, Valérie F. Quesniaux, PhD, Bernhard Ryffel, MD, PhD, Dieudonnée Togbe, PhD  Journal of Allergy and Clinical Immunology  Volume 142, Issue 3, Pages (September 2018) DOI: /j.jaci Copyright © 2018 The Authors Terms and Conditions

2 Journal of Allergy and Clinical Immunology 2018 142, 942-958DOI: (10
Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2018 The Authors Terms and Conditions

3 Fig 1 Epithelial damage, chemokine production, and cell death in BALF on ozone exposure. A, Time course of epithelial cell recruitment and total protein, IL-6, and chemokine (CXCL1, MIP-2, and MCP-1) levels in BALF. B, Neutrophil counts, MPO levels, macrophage counts (both interstitial and alveolar), and TIMP-1 and MMP-9 levels in BALF. C, Total ROS expression and cell death (7-AAD+) in BALF. D, Histologic analysis (hematoxylin and eosin staining) of lung tissue for epithelial damage score. Scale bar = 100 μm. Arrows indicate desquamation. Data are from 3 independent experiments. Values are expressed as means ± SEMs with 5 to 6 mice per group. *P < .05, **P < .01, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2018 The Authors Terms and Conditions

4 Fig 2 IL-33 expression in the lung after ozone exposure. A and B, Time course of pulmonary IL-33 protein expression by using Luminex (Fig 2, A) and cleavage forms by using Western blotting at 24 hours in WT (Fig 2, B). C, Immunofluorescence staining of IL-33 24 hours after ozone exposure, frequency, and mean fluorescence intensity (MFI) of IL-33+ cells in WT mice. Scale bar = 100 μm. DAPI, 4′-6-Diamidino-2-phenylindole dihydrochloride. D and E, Absolute numbers of IL 33–citrine+ cells in BALF and lung tissue on ozone exposure using IL-33 citrine reporter mice at 24 hours. Data are representative of 2 independent experiments. Values are expressed as means ± SEMs with 5 to 6 mice per group. *P < .05, **P < .01, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2018 The Authors Terms and Conditions

5 Fig 3 Ozone-induced lung inflammation is enhanced in Il33– and ST2-deficient mice 24 hours after ozone exposure. A-C, Total cells, neutrophils, and macrophages (Fig 3, A); CXCL1, MPO, and LCN-2; Fig 2, B); and MMP-9, TIMP-1, and AREG (Fig 3, C) in BALF of WT, ST2−/−, and Il33−/− mice. D, Histologic analysis (hematoxylin and eosin staining) of lung tissue and cell infiltration in the peribronchial area and epithelial damage scores in ST2−/− or Il33−/− mice. Scale bar = 100 μm. Arrows indicate cell infiltration. Data are pooled from 4 experiments. Values are expressed as means ± SEMs with 4 to 6 mice per group. *P < .05, **P < .01, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2018 The Authors Terms and Conditions

6 Fig 3 Ozone-induced lung inflammation is enhanced in Il33– and ST2-deficient mice 24 hours after ozone exposure. A-C, Total cells, neutrophils, and macrophages (Fig 3, A); CXCL1, MPO, and LCN-2; Fig 2, B); and MMP-9, TIMP-1, and AREG (Fig 3, C) in BALF of WT, ST2−/−, and Il33−/− mice. D, Histologic analysis (hematoxylin and eosin staining) of lung tissue and cell infiltration in the peribronchial area and epithelial damage scores in ST2−/− or Il33−/− mice. Scale bar = 100 μm. Arrows indicate cell infiltration. Data are pooled from 4 experiments. Values are expressed as means ± SEMs with 4 to 6 mice per group. *P < .05, **P < .01, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2018 The Authors Terms and Conditions

7 Fig 4 ST2 antibody neutralization enhanced inflammatory cell recruitment 24 hours after ozone exposure in WT mice. A, Anti-ST2 or isotype control antibody treatment study scheme. B-D, Total cells, neutrophils, and macrophages (Fig 4, B); CXCL1, MPO, and LCN-2; Fig 4, C); and MMP-9, TIMP-1, and AREG (Fig 4, D) in BALF from WT mice. E, Histologic analysis (hematoxylin and eosin staining) with cell infiltration in the peribronchial area and epithelial damage scores from the lungs of WT mice treated with ST2 neutralizing antibody. Scale bar = 100 μm. Arrows indicate desquamation. Semiquantitative scores are shown. Experiments are pooled of 2 experiments and repeated twice. Values are expressed as means ± SEMs with 5 to 6 mice per group. *P < .05, **P < .01, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2018 The Authors Terms and Conditions

8 Fig 4 ST2 antibody neutralization enhanced inflammatory cell recruitment 24 hours after ozone exposure in WT mice. A, Anti-ST2 or isotype control antibody treatment study scheme. B-D, Total cells, neutrophils, and macrophages (Fig 4, B); CXCL1, MPO, and LCN-2; Fig 4, C); and MMP-9, TIMP-1, and AREG (Fig 4, D) in BALF from WT mice. E, Histologic analysis (hematoxylin and eosin staining) with cell infiltration in the peribronchial area and epithelial damage scores from the lungs of WT mice treated with ST2 neutralizing antibody. Scale bar = 100 μm. Arrows indicate desquamation. Semiquantitative scores are shown. Experiments are pooled of 2 experiments and repeated twice. Values are expressed as means ± SEMs with 5 to 6 mice per group. *P < .05, **P < .01, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2018 The Authors Terms and Conditions

9 Fig 5 Neutrophil depletion attenuates inflammation. GR-1 antibody administration study scheme (A); effect of GR-1 depletion on total cells, neutrophils, macrophages, desquamation (epithelial cell), and cell death (7-AAD+; B); and airways hyperresponsiveness to increasing doses of methacholine (C). Data are pooled from 2 experiments. Values are expressed as means ± SEMs with 5 to 6 mice for air and ozone. i.p., Intraperitoneal. **P < .01 and ****P < .0001. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2018 The Authors Terms and Conditions

10 Fig 6 Ozone-induced disruption of the epithelial barrier is mediated by IL-33/ST2 signaling at 24 hours. Histologic analysis (hematoxylin and eosin staining) of lung sections from WT and ST2−/− mice. Scale bar = 100 μm. A-D, Desquamation (arrows) and injury score (Fig 6, A), epithelial desquamation (Fig 6, B), epithelial barrier permeability with Evans Blue leakage at 24 hours into BALF (Fig 6, C), and airway resistance (Fig 6, D) in WT and ST2−/− mice. E, E-cadherin expression in BALF from rIL-33–treated WT, ST2−/−, and Il33−/− mice 24 hours after exposure. Experimental data are pooled from 2 experiments. Values are expressed as means ± SEMs with 4 to 6 mice per group. F, ZO-1 expression after ozone exposure at 24 hours in WT and ST2−/− mice. Representative images of 1 experiment are shown in the upper panel. Quantification of ZO-1 expression, as depicted in the lower panel, is shown as mean fluorescence intensity from 3 independent experiments. *P < .05, **P < .01, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2018 The Authors Terms and Conditions

11 Fig 6 Ozone-induced disruption of the epithelial barrier is mediated by IL-33/ST2 signaling at 24 hours. Histologic analysis (hematoxylin and eosin staining) of lung sections from WT and ST2−/− mice. Scale bar = 100 μm. A-D, Desquamation (arrows) and injury score (Fig 6, A), epithelial desquamation (Fig 6, B), epithelial barrier permeability with Evans Blue leakage at 24 hours into BALF (Fig 6, C), and airway resistance (Fig 6, D) in WT and ST2−/− mice. E, E-cadherin expression in BALF from rIL-33–treated WT, ST2−/−, and Il33−/− mice 24 hours after exposure. Experimental data are pooled from 2 experiments. Values are expressed as means ± SEMs with 4 to 6 mice per group. F, ZO-1 expression after ozone exposure at 24 hours in WT and ST2−/− mice. Representative images of 1 experiment are shown in the upper panel. Quantification of ZO-1 expression, as depicted in the lower panel, is shown as mean fluorescence intensity from 3 independent experiments. *P < .05, **P < .01, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2018 The Authors Terms and Conditions

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