IL-33 is more potent than IL-25 in provoking IL-13–producing nuocytes (type 2 innate lymphoid cells) and airway contraction Jillian L. Barlow, PhD, Samantha.

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IL-33 is more potent than IL-25 in provoking IL-13–producing nuocytes (type 2 innate lymphoid cells) and airway contraction Jillian L. Barlow, PhD, Samantha Peel, PhD, Jane Fox, PhD, Veera Panova, MRes, Clare S. Hardman, BSc, Ana Camelo, PhD, Christine Bucks, PhD, Xiaoying Wu, MD, Colleen M. Kane, PhD, Daniel R. Neill, PhD, Robin J. Flynn, PhD, Ian Sayers, PhD, Ian P. Hall, DM, Andrew N.J. McKenzie, PhD Journal of Allergy and Clinical Immunology Volume 132, Issue 4, Pages 933-941 (October 2013) DOI: 10.1016/j.jaci.2013.05.012 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 OVA-induced airways resistance. Airway resistance in wild-type and Il17rb−/− (A), Il1rl1−/− (B), and Il17rbIl1rl1−/− (C) mice. **P < .01 and ***P < .001 comparing wild-type PBS- and OVA-treated mice. §P < .05 and §§§P < .001 comparing OVA-treated wild-type and receptor-deficient mice. Data are representative of 2 independent experiments (n = 6-8 mice per group). ns, Not significant. Journal of Allergy and Clinical Immunology 2013 132, 933-941DOI: (10.1016/j.jaci.2013.05.012) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 AHR after ragweed lung challenge. Airways resistance in wild-type and Il17rb−/− (A), Il1rl1−/− (B), and Il17rbIl1rl1−/− (C) mice. *P < .05 and **P < .01 comparing wild-type PBS- and OVA-treated mice. §P < .05 and §§P < .01 comparing OVA-treated wild-type and receptor-deficient mice. Data are representative of 2 independent experiments (n = 6-8 mice per group). ns, Not significant. Journal of Allergy and Clinical Immunology 2013 132, 933-941DOI: (10.1016/j.jaci.2013.05.012) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 IL-33–induced airway contraction ex vivo. A, Lung slices treated with cytokine overnight showing maximal contraction after treatment with 10 μmol/L methacholine. L, Airway lumen. B, Change in luminal area in response to 10 μmol/L methacholine after PBS (n = 25), OVA (n = 15), IL-33 (n = 17), or IL-25 (n = 10) treatment. C and D, Methacholine-induced airway contraction after exposure to PBS or IL-33 in wild-type (n = 27) and Il1rl1−/− (n = 27) mice (Fig 3, C) or in wild-type (n = 6) and Il4−/−Il5−/−Il9−/−Il13−/− (n = 8) mice (Fig 3, D). All data represent slices pooled from at least 2 independent experiments with group sizes of 4, where at least 3 slices were analyzed per mouse. ns, Not significant. Journal of Allergy and Clinical Immunology 2013 132, 933-941DOI: (10.1016/j.jaci.2013.05.012) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 IL-33 is expressed after OVA challenge. A, IL-33 mRNA expression in lung slices (n = 4 mice per group). B and C, Total lung cells (Fig 4, B) and CD45−, CD45+, and CD45−EpCam+ cells; ILC2s (lineage−ICOS+); and T cells (CD3+CD4+) in the lung expressing IL-33Cit (Fig 4, C). D, Quantitative PCR expression of IL-33 in human bronchial epithelial cells (HBEC; 3 patient donors, passages 3-4), human airway smooth muscle (HASM; 5 donors, passages 2-7), and HMC-1 cells. Cycle threshold values were normalized to hypoanthine-guanine phosphoribosyltransferase (n = 2 experiments, 3 repeats within each experiment). Average values for human bronchial epithelial cell expression served as a standard (100% expression) to compare samples. Journal of Allergy and Clinical Immunology 2013 132, 933-941DOI: (10.1016/j.jaci.2013.05.012) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 IL-33 induces potent and rapid production of IL-13eGFP by ILC2s. A, Representative confocal images of lung sections from Il13+/eGFP mice 24 hours after 1 intranasal dose of PBS, IL-25, or IL-33. B, Flow cytometric analysis of IL-13eGFP+ cells gated either as lineage− (top panel) or lineage+ (bottom panel) from treated mice (n = 3-4) from 2 independent experiments. DAPI, 4′-6-Diamidino-2-phenylindole dihydrochloride. Journal of Allergy and Clinical Immunology 2013 132, 933-941DOI: (10.1016/j.jaci.2013.05.012) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 IL-25 and IL-33 expression after RWP lung challenge. Il33+/CitIl13+/Tom mice were treated with 1 intranasal dose of RWP. A and B, At 24 hours, total cells expressing IL-13Tom or IL-33Cit were assessed (Fig 6, A), and representative confocal micrographs from Il33+/CitIl13+/Tom mice were taken (Fig 6, B). C, IL-25 protein levels were measured by means of the Meso-Scale Discovery platform after 1 intranasal dose of RWP. D, IL-25 and IL-33 gene expression compared with glyceraldehyde-3-phosphate dehydrogenase, as measured by using quantitative PCR, in wild-type mice treated with 4 consecutive doses of RWP. Journal of Allergy and Clinical Immunology 2013 132, 933-941DOI: (10.1016/j.jaci.2013.05.012) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2013 132, 933-941DOI: (10.1016/j.jaci.2013.05.012) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2013 132, 933-941DOI: (10.1016/j.jaci.2013.05.012) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2013 132, 933-941DOI: (10.1016/j.jaci.2013.05.012) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2013 132, 933-941DOI: (10.1016/j.jaci.2013.05.012) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Journal of Allergy and Clinical Immunology 2013 132, 933-941DOI: (10.1016/j.jaci.2013.05.012) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Journal of Allergy and Clinical Immunology 2013 132, 933-941DOI: (10.1016/j.jaci.2013.05.012) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E7 Journal of Allergy and Clinical Immunology 2013 132, 933-941DOI: (10.1016/j.jaci.2013.05.012) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Table E2 Journal of Allergy and Clinical Immunology 2013 132, 933-941DOI: (10.1016/j.jaci.2013.05.012) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions