IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen-induced eosinophilic airway inflammation Kentaro Takahashi, MD, Koichi.

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IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen-induced eosinophilic airway inflammation Kentaro Takahashi, MD, Koichi Hirose, MD, PhD, Saki Kawashima, MSc, Yusuke Niwa, Hidefumi Wakashin, MD, PhD, Arifumi Iwata, MD, PhD, Koji Tokoyoda, PhD, Jean-Christophe Renauld, PhD, Itsuo Iwamoto, MD, PhD, Toshinori Nakayama, MD, PhD, Hiroshi Nakajima, MD, PhD Journal of Allergy and Clinical Immunology Volume 128, Issue 5, Pages 1067-1076.e6 (November 2011) DOI: 10.1016/j.jaci.2011.06.018 Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Lung-infiltrating CD4+ T cells produce IL-22 in allergic airway inflammation. OVA-sensitized BALB/c mice were challenged with inhaled OVA or saline (control). IL-22 levels and CD4+ T-cell numbers in BALF were then analyzed at 48 hours after OVA inhalation. A, IL-22 levels are increased in the lungs of sensitized mice on antigen inhalation. The amounts of IL-22 in BALF were determined by means of ELISA. Data are presented as means ± SDs for 5 mice in each group. ∗P < .05. B, IL-22–producing CD4+ T-cell numbers are increased in allergic airway inflammation. CD4+ T cells in BALF or inguinal lymph nodes (control) were collected by means of magnetic cell sorting and analyzed for the expression of CD4 and intracellular IL-22. Representative CD4 versus IL-22 staining of cells from BALF and inguinal lymph nodes (LN) and means ± SDs of the percentage of IL-22+ cells among CD4+ T cells are shown (n = 4 each). ∗P < .05. C, CD4+ T cells in BALF were analyzed for intracellular IL-22 together with IFN-γ, IL-4, and IL-17. D, CD4+ T cells in BALF were analyzed for intracellular IL-22 together with CCR5, CCR3, CCR6, and CCR10. E, Cells in BALF were stained with anti-CD4 antibody and anti–IL-22 antibody. Representative photomicrographs from 4 mice are shown. Journal of Allergy and Clinical Immunology 2011 128, 1067-1076.e6DOI: (10.1016/j.jaci.2011.06.018) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Anti–IL-22 antibody enhances antigen-induced eosinophil and CD4+ T-cell recruitment into the airways. OVA-sensitized BALB/c mice were injected intraperitoneally with polyclonal anti–IL-22 antibody (20 μg per mouse) or control antibody. Twenty-four hours later, the mice were challenged with inhaled OVA or saline. A, Numbers of lymphocytes, eosinophils, neutrophils, and CD4+ T cells in BALF were evaluated at 48 hours after OVA inhalation. Data are presented as means ± SDs for 10 mice in each group. ∗P < .05. B, Levels of IL-5, IL-13, and IFN-γ in BALF were evaluated by means of ELISA at 48 hours after OVA inhalation. Data are presented as means ± SDs for 10 mice in each group. ND, Not determined. ∗P < .05. Journal of Allergy and Clinical Immunology 2011 128, 1067-1076.e6DOI: (10.1016/j.jaci.2011.06.018) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Anti–IL-22 antibody enhances antigen-induced goblet cell hyperplasia and AHR. OVA-sensitized BALB/c mice were injected intraperitoneally with polyclonal anti–IL-22 antibody or control antibody. Twenty-four hours later, the mice were challenged with inhaled OVA 3 times at a 48-hour interval. A, Histologic analysis of the lung was performed with hematoxylin and eosin (HE) and PAS staining at 48 hours after the final OVA inhalation. Representative photomicrographs of lung sections and the number of goblet cells in the airways are shown. Data are presented as means ± SDs for 5 mice in each group. ∗P < .05. B, Airway resistance to acetylcholine was measured at 24 hours after the final OVA inhalation by using the flexiVent system, as described in the Methods section. Data are presented as means ± SDs for 10 mice in each group. ∗P < .05. Journal of Allergy and Clinical Immunology 2011 128, 1067-1076.e6DOI: (10.1016/j.jaci.2011.06.018) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Intranasal administration of IL-22 attenuates antigen-induced eosinophil recruitment into the airways. Recombinant IL-22 (0.1 μg per mouse) or saline was administrated intranasally to OVA-sensitized BALB/c mice twice at 48 hours and 2 hours before the inhaled OVA challenge. Mice were challenged with OVA or saline inhalation, and at 48 hours after inhalation, numbers of lymphocytes, eosinophils, neutrophils, and CD4+ T cells (A) and levels of IL-5, IL-13, and IFN-γ (B) in BALF were evaluated. Data are presented as means ± SDs for 4 mice in each group. ND, Not determined. ∗P < .05. Journal of Allergy and Clinical Immunology 2011 128, 1067-1076.e6DOI: (10.1016/j.jaci.2011.06.018) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Lung epithelial cells express functional IL-22 receptors. A, Lung sections of OVA-sensitized, OVA-inhaled BALB/c mice were stained with anti–IL-22R1 antibody and anti–type 1 collagen antibody. The nuclei were counterstained with TO-PRO-3 iodide. Representative photomicrographs from 3 independent experiments are shown. B, CD4+ T cells, CD8+ T cells, and alveolar macrophages (AM) were purified from BALF at 48 hours after OVA inhalation. BMDCs were prepared as described in the Methods section. cDNA was prepared from CD4+ T cells, CD8+ T cells, alveolar macrophages, BMDCs, and MLE-15 cells, and expression levels of IL-10R2, and IL-22R1 mRNA were analyzed by means of qPCR analysis. Shown are representative data of 4 independent experiments. C, MLE-15 cells were stimulated with indicated cytokines (20 ng/mL) for 15 minutes, and cell lysates were subjected to immunoblotting with anti-phospho-STAT3 (pSTAT3) antibody, anti-phospho-STAT6 (pSTAT6) antibody, or anti-STAT3 antibody. Shown are representative data of 3 independent experiments. Journal of Allergy and Clinical Immunology 2011 128, 1067-1076.e6DOI: (10.1016/j.jaci.2011.06.018) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Anti–IL-22 antibody enhances antigen-induced IL-25 production in the airways. A and B, OVA-sensitized BALB/c mice were injected intraperitoneally with anti–IL-22 antibody or control antibody. Twenty-four hours later, the mice were challenged with inhaled OVA or saline. Fig 6, A, Expression of eotaxin-1 and TARC mRNA in the lung tissue was evaluated at 48 hours after OVA inhalation determined by mean of qPCR analysis. Data are presented as means ± SDs for 5 mice in each group. Fig 6, B, Levels of TSLP, IL-25, and IL-33 in BALF were evaluated by means of ELISA at 48 hours after OVA inhalation. Data are presented as means ± SDs for 5 mice in each group. ND, Not determined. ∗P < .05. C, MLE-15 cells were stimulated with IL-1β (20 ng/mL), LPS (100 ng/mL), and/or IL-13 (20 ng/mL) in the presence or absence of IL-22 (20 ng/mL) for 6 hours. The expression of IL-25 mRNA was evaluated by means of qPCR. Data shown are representative of 4 independent experiments. Journal of Allergy and Clinical Immunology 2011 128, 1067-1076.e6DOI: (10.1016/j.jaci.2011.06.018) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Anti–IL-25 antibody reverses the enhancing effect of anti–IL-22 antibody on antigen-induced airway inflammation. OVA-sensitized BALB/c mice were injected intraperitoneally with anti–IL-22 antibody, anti–IL-25 antibody, or both (20 μg per mouse) at 24 hours before OVA inhalation. Numbers of eosinophils and lymphocytes in BALF were evaluated at 48 hours after OVA inhalation. Data are presented as means ± SD for 5 mice in each group. ∗P < .05. Journal of Allergy and Clinical Immunology 2011 128, 1067-1076.e6DOI: (10.1016/j.jaci.2011.06.018) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Lung-infiltrating CD4+ cells but not CD4+CD3ε− cells express IL-22 mRNA in allergic airway inflammation. OVA-sensitized BALB/c mice were challenged with inhaled OVA. Forty-eight hours after inhalation, CD4+, CD8+, B220+, DX5+, CD11c+, and CD4+CD3ε− cells were isolated from lung homogenates by means of magnetic cell sorting, and qPCR analysis for IL-22 was performed. Representative data from 4 independent experiments are shown. Journal of Allergy and Clinical Immunology 2011 128, 1067-1076.e6DOI: (10.1016/j.jaci.2011.06.018) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Intranasal administration of IL-22 tends to attenuate airway hyperreactivity. OVA-sensitized BALB/c mice were challenged with inhaled OVA 3 times at a 48-hour interval. Recombinant IL-22 (0.1 μg per mouse) or saline was administrated intranasally to the mice 2 hours before each OVA inhalation. Twenty-four hours after the last OVA inhalation, airway resistance to acetylcholine was evaluated. Data are presented as means ± SDs for 4 mice in each group. Journal of Allergy and Clinical Immunology 2011 128, 1067-1076.e6DOI: (10.1016/j.jaci.2011.06.018) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Intranasal administration of IL-22 accelerates the resolution of allergic airway inflammation. OVA-sensitized BALB/c mice were challenged with inhaled OVA 3 times at a 48-hour interval. IL-22 (0.1 μg per mouse) or saline was administered intranasally to the mice 3 times at 24, 48, and 72 hours after the last OVA inhalation. Four hours alter the last IL-22 administration, numbers of eosinophils and lymphocytes and levels of IL-5 and IL-13 in BALF were evaluated. Data are presented as means ± SDs (n = 5 each). ∗P < .05. Journal of Allergy and Clinical Immunology 2011 128, 1067-1076.e6DOI: (10.1016/j.jaci.2011.06.018) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 IL-22 induces SOCS3 mRNA in MLE-15 cells. MLE-15 cells were stimulated with IL-22 (20 ng/mL) for indicated time periods, and the expression of SOCS3 mRNA was evaluated by means of qPCR analysis. Data are presented as means ± SDs (n = 4 in each group). ∗P < .05. Journal of Allergy and Clinical Immunology 2011 128, 1067-1076.e6DOI: (10.1016/j.jaci.2011.06.018) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Anti–IL-25 antibody tends to reverse the enhancing effect of anti–IL-22 antibody on antigen-induced IL-13 production in the airways. OVA-sensitized BALB/c mice were injected intraperitoneally with anti–IL-22 antibody (20 μg per mouse), anti–IL-25 antibody (20 μg per mouse), or both at 24 hours before OVA inhalation. Levels of IL-13 in BALF were evaluated at 48 hours after OVA inhalation. Data are presented as means ± SDs (n = 5 mice per group). ∗P < .05. Journal of Allergy and Clinical Immunology 2011 128, 1067-1076.e6DOI: (10.1016/j.jaci.2011.06.018) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions