Stephan Löser, MSc, Lisa G

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Presentation transcript:

Pulmonary ORMDL3 is critical for induction of Alternaria-induced allergic airways disease Stephan Löser, MSc, Lisa G. Gregory, PhD, Youming Zhang, PhD, Katrein Schaefer, PhD, Simone A. Walker, MSc, James Buckley, PhD, Laura Denney, PhD, Charlotte H. Dean, PhD, William O.C. Cookson, MD, DPhil, Miriam F. Moffatt, DPhil, Clare M. Lloyd, PhD Journal of Allergy and Clinical Immunology Volume 139, Issue 5, Pages 1496-1507.e3 (May 2017) DOI: 10.1016/j.jaci.2016.07.033 Copyright © 2016 The Authors Terms and Conditions

Journal of Allergy and Clinical Immunology 2017 139, 1496-1507 Journal of Allergy and Clinical Immunology 2017 139, 1496-1507.e3DOI: (10.1016/j.jaci.2016.07.033) Copyright © 2016 The Authors Terms and Conditions

Fig 1 Ormdl3 KOMer mice are protected from developing Alternaria-induced AHR. A, Expression of Ormdl1 to Ormdl3 in lungs of naive WT and KO mice by quantitative PCR. B, Experimental plan (C-H). Lung function measured using the FlexiVent system. Dose-response curve to methacholine showing (Fig 1, C) airway resistance, (Fig 1, E) airway elastance, and (Fig 1, G) airway compliance. Airway resistance (Fig 1, D), airway elastance (Fig 1, F), and airway compliance (Fig 1, H) at 200 mg/mL methacholine. I, Concentration-response curve of tracheas toward increasing concentrations of methacholine. J, EC50 values of contraction responses. Alt, Alternaria; BL, baseline; i.n., intranasal; Data were collected from 2 individually performed experiments. N = 8-12 mice per group. Box and whisker plots depict the median and interquartile range and minimum and maximum values. *P < .05, **P < .005, and ***P < .0005. Journal of Allergy and Clinical Immunology 2017 139, 1496-1507.e3DOI: (10.1016/j.jaci.2016.07.033) Copyright © 2016 The Authors Terms and Conditions

Fig 2 Analysis of Alternaria-induced AAD in WT and Ormdl3 KOMer mice. A, Lung total cell counts. B, Alternaria-induced pulmonary inflammation in tissue sections (H&E staining). C, BALF total cell counts. D, Eosinophils expressed as the percentage SiglecF+ CD11c− CD68− lung cells. E, Total IgE concentration. F, Alternaria-specific IgE concentration. Representative photomicrographs are shown. Original magnification ×20. Alt, Alternaria; H&E, hematoxylin & eosin. Data were collected from 2 individually performed experiments. N = 8-16 mice per group. Box and whisker plots depict the median and interquartile range and minimum and maximum values. *P < .05, **P < .005, and ***P < .0005. Journal of Allergy and Clinical Immunology 2017 139, 1496-1507.e3DOI: (10.1016/j.jaci.2016.07.033) Copyright © 2016 The Authors Terms and Conditions

Fig 3 ORMDL3 does not influence Alternaria-induced type 2 inflammation or mediators. A, Pulmonary TH2 cells (IL-13+ CD4+ CD3+). B, ILC2 cells (IL-13+ ICOS+ CD45+ lineage− cells). IL-13 (C), IL-4 (D), IL-5 (E), and IL-33 (F) cytokine levels in lung tissue determined by ELISA. Alt, Alternaria. Data were collected from 2 individually performed experiments. N = 8-16 mice per group. Box and whisker plots depict the median and interquartile range and minimum and maximum values. ILC2, Type 2 innate lymphoid cell. *P < .05, **P < .005, and ***P < .0005. Journal of Allergy and Clinical Immunology 2017 139, 1496-1507.e3DOI: (10.1016/j.jaci.2016.07.033) Copyright © 2016 The Authors Terms and Conditions

Fig 4 Ormdl3 KOMer mice have diminished cellular stress responses to Alternaria. A, Schematic showing major components of the UPR. B, Western blot showing p-eIF2α. Specific quantitative PCR analyses were performed for Atf4 (C), Ddit3 (D), and total Xbp1 (E). F, PCR of total and spliced Xbp1. G, Edem1 quantitative PCR. H, IL-6 determined by ELISA. I, Western blot showing SERCA2b. Uric acid (J), LDH (K), and albumin (L) levels in BALF. Alt, Alternaria; Ddit3, DNA-damage-inducible transcript 3; Edem1, ER degradation enhancer, mannosidase alpha-like 1. Data were collected from 2 individually performed experiments. N = 8-16 mice per group. Box and whisker plots depict the median and interquartile range and minimum and maximum values. *P < .05, **P < .005, and ***P < .0005. For analysis of gene expression, Mann-Whitney statistical tests were performed between groups where a greater than 2-fold induction of median values was observed. Journal of Allergy and Clinical Immunology 2017 139, 1496-1507.e3DOI: (10.1016/j.jaci.2016.07.033) Copyright © 2016 The Authors Terms and Conditions

Fig 5 ORMDL3 overexpression in airway epithelial cells enhances AHR. A, Experimental plan. B, GFP expression (staining green) in the lungs. C-E, Lung function measured using the FlexiVent system. Fig 5, C, Dose-response curve to methacholine showing airway resistance. Airway resistance at baseline (Fig 5, D) and 30 mg/mL methacholine (Fig 5, E). F, Total cells in the BALF. G, Eosinophils. Alt, Alternaria; Representative photomicrographs are shown. Original magnification ×20. Data were collected from 3 individually performed experiments. N = 8-12 mice per group. Box and whisker plots depict the median and interquartile range and minimum and maximum values. *P < .05, **P < .005, and ***P < .0005. Journal of Allergy and Clinical Immunology 2017 139, 1496-1507.e3DOI: (10.1016/j.jaci.2016.07.033) Copyright © 2016 The Authors Terms and Conditions

Fig 6 Epithelial ORMDL3 expression drives susceptibility to Alternaria-induced AHR. A, Ormdl3 expression in epithelial (EpCam+) cells and leukocytes (CD45+) sorted from WT mice. B, GFP expression (staining green) in the lungs. C, EGFP expression in sorted epithelial cells and leukocytes from Ormdl3 KOHar mice following administration of either AAV EGFP or AAV Ormdl3. D, Experimental plan. E, Total cells in the BALF. F, Uric acid concentration. G-L, Lung function measured using the FlexiVent system. Airway resistance (Fig 6, G and J), airway elastance (Fig 6, H and K), and airway compliance (Fig 6, I and L). M, Albumin levels determined in BALF. Alt, Alternaria; i.n., intranasal. Representative photomicrographs are shown. Original magnification ×20. Data were collected from 2 individually performed experiments. N = 7-12 mice per group. Box and whisker plots depict the median and interquartile range and minimum and maximum values. *P < .05, **P < .005, and ***P < .0005. Journal of Allergy and Clinical Immunology 2017 139, 1496-1507.e3DOI: (10.1016/j.jaci.2016.07.033) Copyright © 2016 The Authors Terms and Conditions

Fig E1 Comparative schematic of strategies used to generate Ormdl3MER KO and Ormdl3HAR KO mice. A, Strategy used by MERCK. The gene Ormdl3 contains 4 exons of which exons 2 to 4 are encoding the ORMDL3 protein. Exons 2 to 4 were consequently flanked by 2 antibiotic selection cassettes (Puro, puromycin; Neo, neomycin) and loxP recombination sites were inserted upstream of the Puro cassette and downstream of the Neo cassette. Following homologous recombination, Flp recombination, and Cre recombination steps, the resulting Ormdl3MER KO strain retains a loxP recombination site downstream of exon 1. B, The approach used by MRC Harwell slightly differed from the MERCK strategy, as a single neomycin selection cassette was included in the targeting vector. LoxP recombination sites were located between exons 1 and 2 and between exon 4 and the FRT-flanked Neo cassette. The resulting Ormdl3HAR KO mice strain therefore retains a loxP, as well as an FRT recombination site after homologous, Flp and Cre recombination. CDS, Coding sequence; UTR, untranslated region. Journal of Allergy and Clinical Immunology 2017 139, 1496-1507.e3DOI: (10.1016/j.jaci.2016.07.033) Copyright © 2016 The Authors Terms and Conditions

Fig E2 Effect of epithelial ORMDL3 expression on type 2 inflammation. A, TH2 cells (IL-13+ CD4+ CD3+) in the BALF. B, Eosinophils expressed as the percentage SiglecF+ CD11c− CD68− in the BALF. C, IL-13 levels in the BALF. Serum IgE levels (D) and lactate dehydrogenase levels (E) in the BALF. Alt, Alternaria. Data were combined from 2 individually performed experiments. N = 7-12 mice per group. Box and whisker plots depict the median and interquartile range and minimum and maximum values. *P < .05, **P < .005, and ***P < .0005. Journal of Allergy and Clinical Immunology 2017 139, 1496-1507.e3DOI: (10.1016/j.jaci.2016.07.033) Copyright © 2016 The Authors Terms and Conditions