Weiguo Chen, PhD, Umasundari Sivaprasad, PhD, Aaron M

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IL-13 receptor α2 contributes to development of experimental allergic asthma Weiguo Chen, PhD, Umasundari Sivaprasad, PhD, Aaron M. Gibson, BS, Mark B. Ericksen, BS, Christie M. Cunningham, BS, Stacey A. Bass, Kayla G. Kinker, BS, Fred D. Finkelman, MD, Marsha Wills-Karp, PhD, Gurjit K. Khurana Hershey, MD, PhD Journal of Allergy and Clinical Immunology Volume 132, Issue 4, Pages 951-958.e6 (October 2013) DOI: 10.1016/j.jaci.2013.04.016 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 HDM-induced AHR and airway inflammation in wild-type and IL-13Rα2–deficient mice. Data are shown as means ± SDs. A, APTI of PBS- or HDM-treated wild-type and IL-13Rα2–deficient mice (n = 8-10). B, Total cells and eosinophils in BAL samples of PBS- or HDM-treated wild-type and IL-13Rα2–deficient mice (n = 8-10). KO, IL-13Rα2 deficient; WT, wild type. *P < .05 and ***P < .001. Journal of Allergy and Clinical Immunology 2013 132, 951-958.e6DOI: (10.1016/j.jaci.2013.04.016) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 HDM-induced AHR and airway inflammation in nontransgenic and memIL-13Rα2 transgenic mice. Mice were sensitized and challenged with PBS or HDM. Data are shown as means ± SDs. A, APTI of PBS- or HDM-treated nontransgenic mice and memIL-13Rα2 transgenic mice (n = 4-5). B, Total cells and eosinophils in BAL samples from PBS- or HDM-treated nontransgenic mice and memIL-13Rα2 transgenic mice (n = 4-5). C, APTI of PBS- or HDM-treated wild-type, IL-13Rα2-deficient, and memIL-13Rα2 transgenic/IL-13Rα2-deficient mice (n = 5-8). D, Serum total IgE levels in PBS- or HDM-treated wild-type, IL-13Rα2-deficient, and memIL-13Rα2 transgenic/IL-13Rα2-deficient mice (n = 5-8). KO, IL-13Rα2-deficient; NTG, nontransgenic; TG, memIL-13Rα2 transgenic; TG/KO, memIL-13Rα2 transgenic/IL-13Rα2-deficient; WT, wild type. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2013 132, 951-958.e6DOI: (10.1016/j.jaci.2013.04.016) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Hematoxylin and eosin staining of lung sections from PBS- or HDM-treated wild-type, IL-13Rα2-deficient, and memIL-13Rα2 transgenic/IL-13Rα2-deficient mice. KO, IL-13Rα2-deficient; TG/KO, memIL-13Rα2 transgenic/IL-13Rα2-deficient; WT, wild type. Journal of Allergy and Clinical Immunology 2013 132, 951-958.e6DOI: (10.1016/j.jaci.2013.04.016) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Lung mucus production in HDM-treated wild-type, IL-13Rα2–deficient, and memIL-13Rα2 transgenic/IL-13Rα2-deficient mice. A, PAS staining of lung sections. B and C, Western blot analysis and quantification of CLCA3 expression in lung homogenates (n = 3). Lane 1, WT PBS; lane 2, KO PBS; lane 3, TG/KO PBS; lanes 4 and 5, WT HDM; lanes 6 and 7, KO HDM; lanes 8 and 9, TG/KO HDM. D, mRNA expression of Muc5ac in lungs (n = 9-10). E, Muc5ac levels in BALF (n = 9-10). KO, IL-13Rα2-deficient; ns, not significant; TG/KO, memIL-13Rα2 transgenic/IL-13Rα2-deficient; WT, wild type. Data are shown as means ± SDs. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2013 132, 951-958.e6DOI: (10.1016/j.jaci.2013.04.016) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Lung mRNA expression of cytokines and chemokines in production in HDM-treated wild-type, IL-13Rα2-deficient, and memIL-13Rα2 transgenic/IL-13Rα2-deficient mice. A, IL-13. B, IL-4. C, IFN-γ. D, Eotaxin. E, Macrophage-derived chemokine (MDC). F, Thymus and activation-regulated chemokine (TARC). Data are shown as means ± SDs (n = 4-6). KO, IL-13Rα2-deficient; ns, not significant; TG/KO, memIL-13Rα2 transgenic/IL-13Rα2-deficient; WT, wild type. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2013 132, 951-958.e6DOI: (10.1016/j.jaci.2013.04.016) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Characterization of memIL-13Rα2 lung transgenic mice. A, Schematic diagram of the construct for memIL-13Rα2 lung transgenic mice. B, Southern blot analysis of the memIL-13Rα2–hGH transgene in transgenic and nontransgenic mice. The control plasmid was used to estimate transgene copy numbers. C, Northern blot analysis of memIL-13Rα2 expression in the lung. D, RT-qPCR: lung expression of IL-13Rα2. Data are shown as means ± SDs (n = 3). E, ELISA for IL-13Rα2 in lung lysate from memIL-13Rα2 transgenic and nontransgenic mice. Data are shown as means ± SDs (n = 5). *P < .05 and **P < .01. NTG, Nontransgenic; TG, memIL-13Rα2 transgenic. Journal of Allergy and Clinical Immunology 2013 132, 951-958.e6DOI: (10.1016/j.jaci.2013.04.016) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Serum HDM-specific IgE in PBS- or HDM-treated memIL-13Rα2 transgenic/IL-13Rα2-deficient mice. Serum HDM-specific IgE levels were determined by using ELISA. KO, IL-13Rα2-deficient; ns, not significant; TG/KO, memIL-13Rα2 transgenic/IL-13Rα2-deficient; WT, wild type. Data are shown as means ± SDs (n = 9-10). Journal of Allergy and Clinical Immunology 2013 132, 951-958.e6DOI: (10.1016/j.jaci.2013.04.016) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Levels of sIL-13Rα2 in PBS- or HDM-treated memIL-13Rα2 transgenic/IL-13Rα2-deficient mice. A, Serum. B, BALF. Data are shown as means ± SDs (n = 4-8). KO, IL-13Rα2-deficient; TG/KO, memIL-13Rα2 transgenic/IL-13Rα2-deficient; WT, wild type. ***P < .001. Journal of Allergy and Clinical Immunology 2013 132, 951-958.e6DOI: (10.1016/j.jaci.2013.04.016) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Percentage of IL-13–bound and free IL-13Rα2 in BALF and serum of PBS- or HDM-treated nontransgenic and memIL-13Rα2 transgenic mice (n = 5). A, BALF. B, Serum. NTG, Nontransgenic; TG, memIL-13Rα2 transgenic. Journal of Allergy and Clinical Immunology 2013 132, 951-958.e6DOI: (10.1016/j.jaci.2013.04.016) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 mRNA expression of IL-13Rα1 and IL-4Rα in lungs of PBS- or HDM-treated IL-13Rα2 transgenic and nontransgenic mice. A-C, Expression of IL-13Rα1, IL-4Rα, and the hGH transgene in lungs of PBS- or HDM-treated memIL-13Rα2 transgenic and nontransgenic mice. D, Relative expression of IL-13Rα2 to IL-13Rα1. Data are shown as means ± SDs (n = 3-5). ***P < .001. Journal of Allergy and Clinical Immunology 2013 132, 951-958.e6DOI: (10.1016/j.jaci.2013.04.016) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 IL-13–induced STAT6 activation in lungs from nontransgenic and memIL-13Rα2 transgenic mice. A, Nuclear extracts from lungs of IL-13–treated nontransgenic and memIL-13Rα2 transgenic mice at different time points (1, 2, 4, 8, 16, and 24 hours) were used to assess STAT6 DNA-binding activity by using EMSA. B, Quantification of STAT6 activity. Data are shown as means ± SDs (n = 3). NTG, Nontransgenic; TG, memIL-13Rα2 transgenic. Journal of Allergy and Clinical Immunology 2013 132, 951-958.e6DOI: (10.1016/j.jaci.2013.04.016) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions