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Neonatal rhinovirus induces mucous metaplasia and airways hyperresponsiveness through IL-25 and type 2 innate lymphoid cells  Jun Young Hong, MS, J. Kelley.

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Presentation on theme: "Neonatal rhinovirus induces mucous metaplasia and airways hyperresponsiveness through IL-25 and type 2 innate lymphoid cells  Jun Young Hong, MS, J. Kelley."— Presentation transcript:

1 Neonatal rhinovirus induces mucous metaplasia and airways hyperresponsiveness through IL-25 and type 2 innate lymphoid cells  Jun Young Hong, MS, J. Kelley Bentley, PhD, Yutein Chung, PhD, Jing Lei, BS, Jessica M. Steenrod, BS, Qiang Chen, BS, Uma S. Sajjan, PhD, Marc B. Hershenson, MD  Journal of Allergy and Clinical Immunology  Volume 134, Issue 2, Pages e8 (August 2014) DOI: /j.jaci Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Cytokine expression after rhinovirus (RV) infection. A and B, Six-day-old and 8-week-old mice were inoculated with sham or rhinovirus (n = 4-8 sham, n = 5-14 rhinovirus), and lung mRNA expression was measured 1 to 7 days later. *P < .05 compared with sham (unpaired t test). C and D, Mice of different ages (n = 3-10 per group) were inoculated with sham or rhinovirus, and mRNA expression was measured 1 day later. *P < .05 versus sham (unpaired t test). Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Mucous metaplasia and airways hyperresponsiveness after neonatal rhinovirus (RV) infection. A, Time course of lung IL-13 levels from mice infected at 6 days of age. *P < .05 versus sham (unpaired t test). B, Periodic acid–Schiff–stained lung sections prepared 3 weeks after inoculation of 6-day-old and 8-week-old mice (magnification ×100). Bar = 200 μm. C, Airway responsiveness 4 weeks after inoculation of neonatal mice (n = 4 per group). *P < .05 versus sham (2-way ANOVA). D and E, Lung mRNA expression 3 weeks after inoculation. *P < .05 versus sham (unpaired t test). Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Lung IL-25 levels after rhinovirus (RV) infection. A, Six-day-old and 8-week-old mice were inoculated with sham or rhinovirus (n = 4-7 per group), and mRNA expression was measured 1 to 7 days after infection. *P < .05 versus sham (unpaired t test). B, IL-25 protein. *P ≤ .05 versus sham (1-way ANOVA). C, Mice were inoculated at different ages (n = 3-10 per group), and mRNA expression was measured 1 day after treatment. *P < .05 versus sham (unpaired t test). D, Two days after infection, lungs were stained for IL-25 (green), rhinovirus (red), and nuclei (4′-6-diamidino-2-phenylindole dihydrochloride [DAPI], black). Bar = 200 μm; magnification ×200. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 Lung Lin−CD25+CD127+ ILC2s. A, Six-day-old and 8-week-old mice were inoculated with sham or rhinovirus (RV), and live ILC2s were identified 14 days later. FSC, Forward scatter; SSC, side scatter. B, Percentage (upper panel) and total (lower panel) ILC2s for each group. *P < .05 versus sham and †P < .05 versus mature mice (unpaired t test). C, c-Kit/CD117, Sca-1, T1/ST2/ST2L and IL-17RB expression in ILC2s from sham-treated (black dotted line) and RV-treated mice (red solid line). The isotype control is shown as the gray filled area. D, ILC2 time course after neonatal infection (n = 3-6 per group). *P < .05 versus sham (unpaired t test). Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 IL-13–producing cells. A, Percentages of IL-13+, TCRβ−, and TCRβ+ cells 2 weeks after neonatal sham or rhinovirus (RV) treatment. *P < .05 versus sham and †P < .05 versus TCRβ− cells (unpaired t test). B and C, Percentages of Lin+ and Lin−IL-13+ cells (Fig 5, B). Percentages of Lin−, IL-13+, CD127+, and CD25+ cells (Fig 5, C). D-F, Eight days after infection, Lin−CD25+CD127+ double-positive (DP) and Lin−CD25−CD127− double-negative (DN) ILC2s were characterized for c-kit and Sca-1 (Fig 5, D). Fig 5, E, shows the image of an ILC2. Fig 5, F, shows IL-13 production by stimulated DP and DN cells. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 Effect of IL-25 neutralization on rhinovirus (RV)–infected neonatal mice. A, Protocol for anti–IL-25 treatment. B, Three weeks after inoculation, lungs were harvested and stained with periodic acid–Schiff. Bar = 100 μm. C, Lung mRNA expression (n = 4-10 per group). *P < .05 versus sham and †P < .05 versus rhinovirus plus IgG (unpaired t test). D, Airway resistance 4 weeks after rhinovirus infection and antibody treatment (n = 4-5 in each group). *P < .05 versus rhinovirus plus IgG (2-way ANOVA). E, Lin−CD25+CD127+ double-positive ILC2s 4 weeks after infection (top). Group percentages of live ILC2s (n = 3-8 per group, bottom). *P < .05 versus sham and †P < .05 versus rhinovirus plus IgG (unpaired t test). Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig E1 Viral copy number in rhinovirus (RV)–infected neonatal and adult mice. Six-day-old and 8-week-old mice were inoculated with sham or rhinovirus intranasally. At specified times, lungs were harvested for analysis. Viral copy number was analyzed by using quantitative PCR. Shown are individual data, medians, and interquartile ranges for each time point. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig E2 Persistent expression of mucus-related gene expression in 8-week-old mice infected with rhinovirus (RV). Gene expression of Muc5ac, Muc5b, Gob5, and Il13 was analyzed with quantitative PCR. *P < .05 versus sham (unpaired t test). Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 Fig E3 Effect of rhinovirus (RV) infection on expression of IL-33. Six-day-old neonatal BALB/c mice and 8-week-old mature mice were inoculated with sham or rhinovirus. Whole-lung gene expression of Il33 was measured by using quantitative PCR 1 to 7 days after infection. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Fig E4 Effect of low-dosage rhinovirus infection in the induction of IL-25 and IFN-γ. Six-day-old neonatal BALB/c mice were inoculated with sham, rhinovirus (normal dosage), or rhinovirus (10-fold lower dosage). Whole-lung mRNA expression was measured by using quantitative PCR 1 day after infection. *P < .05 versus sham (unpaired t test). Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

12 Fig E5 Lin− cells in immature and mature mice. Six-day-old neonatal BALB/c mice and 8-week-old mature mice were inoculated with sham or rhinovirus (RV). Lungs were collected 14 days after infection. Cell suspensions were stained with a cocktail of lineage antibodies (CD3ε, TCRβ, B220/CD45R, Ter-119, Gr-1/Ly-6G/Ly-6C, CD11b, CD11c, F4/80, and FcεRIα) and subjected to flow cytometry. The percentage of Lin− live cells was calculated. †P < .05 versus neonates (unpaired t test). Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

13 Fig E6 Gating strategy for sorting ILC2s. Six-day-old neonatal BALB/c mice were infected with rhinovirus. After 8 days, lungs were processed for cell sorting. Low forward scatter (FSC), low side scatter (SSC), 4′-6-diamidino-2-phenylindole dihydrochloride–negative live cells were gated and incubated with lineage cocktail antibodies (CD3ε, TCRβ, B220/CD45R, Ter-119, Gr-1/Ly-6G/Ly-6C, CD11b, CD11c, F4/80, and FcεRIα) to sort ILC2s. Finally, CD25 and CD127 double-positive cells were identified. DN, Double negative; DP, double positive. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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