Allergic airway disease is unaffected by the absence of IL-4Rα–dependent alternatively activated macrophages Natalie E. Nieuwenhuizen, PhD, Frank Kirstein,

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Presentation transcript:

Allergic airway disease is unaffected by the absence of IL-4Rα–dependent alternatively activated macrophages Natalie E. Nieuwenhuizen, PhD, Frank Kirstein, PhD, Jaisubash Jayakumar, MSc, Babele Emedi, MSc, Ramona Hurdayal, MSc, William G.C. Horsnell, PhD, Andreas L. Lopata, PhD, Frank Brombacher, PhD Journal of Allergy and Clinical Immunology Volume 130, Issue 3, Pages 743-750.e8 (September 2012) DOI: 10.1016/j.jaci.2012.03.011 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 A, mRNA expression in alveolar macrophages (chronic OVA model). Expression was normalized by using the housekeeping gene RPS12 and is shown as fold difference to the PBS group. Data are representative of 2 experiments with triplicate pooled samples. B, Arginase activity and NO production by alveolar macrophages. C, Ym-1 expression on alveolar and interstitial macrophages. **P < .05; ***P < .001, compared with littermate controls. MFI, Mean fluorescence intensity. Journal of Allergy and Clinical Immunology 2012 130, 743-750.e8DOI: (10.1016/j.jaci.2012.03.011) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Resistance (A) and elastance (B) in acute OVA-induced allergic airway disease. N = 8 to 11 mice, pooled data from 2 experiments. Resistance (C) and elastance (D) in chronic OVA-induced allergic airway disease. N = 12 to 16 mice, pooled data from 3 experiments. Significant differences to IL-4Rα−/lox PBS: *P < .05, ***P < .001. P values: Comparison of dose-response curves to inhaled methacholine. Journal of Allergy and Clinical Immunology 2012 130, 743-750.e8DOI: (10.1016/j.jaci.2012.03.011) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Lung pathology (chronic model). A, Mucus hypersecretion and inflammation around airways. Arrows indicate mucus hypersecretion. B, Collagen deposition around airways and blood vessels illustrated by Sirius red staining. Arrows indicate collagen deposition. C, Total lung cells. D, Mucus quantification. E, Collagen quantification. Representative of 3 experiments (n = 4-6 each). Significance versus PBS control: **P < .01, ***P < .001. Journal of Allergy and Clinical Immunology 2012 130, 743-750.e8DOI: (10.1016/j.jaci.2012.03.011) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Eosinophils (Eos) and neutrophils (Neu) in BAL fluid (n = 5-6) after acute (A) and chronic (B) OVA-induced allergic airway disease. C, Numbers of eosinophils in the lungs (n = 5) after chronic OVA exposure. Significant differences to IL-4Rα−/lox PBS are represented by stars (*P < .05, **P < .01, ***P < .001). Journal of Allergy and Clinical Immunology 2012 130, 743-750.e8DOI: (10.1016/j.jaci.2012.03.011) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Antibody and cytokine production in chronic OVA-induced allergic airway disease. A, Total and OVA-specific IgE (n = 5). B, Number of cytokine-producing lung CD4+ T cells (n = 3-5). Significant differences to IL-4Rα−/lox PBS: *P < .05, **P < .01, ***P < .001. Significant differences to IL-4Rα−/lox OVA: #P < .05, ##P < .01. Representative of 2 experiments. Journal of Allergy and Clinical Immunology 2012 130, 743-750.e8DOI: (10.1016/j.jaci.2012.03.011) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Impairment of IL-4Rα expression on macrophages of OVA-challenged lungs of LysMcreIL-4Rα−/lox mice (chronic model). Similar results were observed in the acute model. Representative of 3 individual mice for each strain. IL-4Rα expression was evaluated by flow cytometry on alveolar macrophages (CD11c+SiglecF+), interstitial macrophages (F480+CD11c−SiglecF−), inflammatory macrophages (CD11b+MHCII+CD11c−), monocytes (Lyc6C+CD11b+CD11c−), neutrophils (GR-1 high CD11c−), and dendritic cells (CD11c+MHCII+SiglecF−). MFI, Mean fluorescence intensity. Journal of Allergy and Clinical Immunology 2012 130, 743-750.e8DOI: (10.1016/j.jaci.2012.03.011) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 A, Immunohistochemical staining of Ym-1–positive cells in the lung. B, Quantification of Ym-1–positive cells in the alveolar spaces. Ym-1–positive cells in the alveolar spaces were quantified in 10 fields of view per lung section for each mouse at ×400 magnification (n = 6 per group). Significant difference to IL-4Rα−/lox OVA group: ***P < .001. Journal of Allergy and Clinical Immunology 2012 130, 743-750.e8DOI: (10.1016/j.jaci.2012.03.011) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Lung pathology in the acute OVA model. A, Lung sections were stained with periodic acid-Schiff for mucus. B, Lungs were digested and total lung cells were counted (n = 4-6). C, Mucus was quantified in whole lungs by using NIS Elements. One lung section was quantified per individual mouse. Representative of 2 experiments pooled (n = 7-9). ∗P < .05, ∗∗P < .01, ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2012 130, 743-750.e8DOI: (10.1016/j.jaci.2012.03.011) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Immune cell populations in the lungs (n = 5) after chronic OVA exposure. A, Neutrophils (GR-1 high CD11c−). B, T helper cells (CD3+CD4+). C, Cytotoxic T cells (CD3+CD8+). D, B cells (CD19+CD3−). E, Alveolar macrophages (CD11c+SiglecF+GR-1int). F, Dendritic cells (CD11c+SiglecF−). Significant differences to IL-4Rα−/lox PBS are represented by stars (∗P < .05, **P < .01, ***P < .001). Journal of Allergy and Clinical Immunology 2012 130, 743-750.e8DOI: (10.1016/j.jaci.2012.03.011) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 OVA-specific IgG antibodies in mice sensitized and challenged with OVA (chronic model). Journal of Allergy and Clinical Immunology 2012 130, 743-750.e8DOI: (10.1016/j.jaci.2012.03.011) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 HDM-induced allergic airway disease. A, Eosinophils and neutrophils in BAL fluid (n = 3-6). B, Total IgE (n = 4-6). C, Airway mucus secretion and inflammation (periodic acid-Schiff staining). D, AHR (n =9-11, pooled data from 2 experiments). E, Number of cytokine-producing lung CD4+ T cells. Significant differences to IL-4Rα−/lox PBS: *P < .05, **P < .01, ***P < .001. Journal of Allergy and Clinical Immunology 2012 130, 743-750.e8DOI: (10.1016/j.jaci.2012.03.011) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions