Inhibition of house dust mite–induced allergic airways disease by antagonism of microRNA-145 is comparable to glucocorticoid treatment Adam Collison,

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Inhibition of house dust mite–induced allergic airways disease by antagonism of microRNA-145 is comparable to glucocorticoid treatment Adam Collison, B BioMedSci (Hons), Joerg Mattes, MD, Maximilian Plank, Dipl Biol, Paul S. Foster, PhD Journal of Allergy and Clinical Immunology Volume 128, Issue 1, Pages 160-167.e4 (July 2011) DOI: 10.1016/j.jaci.2011.04.005 Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 miRNA expression is increased in the airway wall of HDM-sensitized and aeroallergen-challenged mice, and tissue levels are decreased by specific antagomirs. Mice were sensitized to HDM. Twelve days later they were exposed to 4 consecutive low-dose HDM challenges and killed 24 hours after the final challenge for analysis. Mice were treated with either antagomir, dexamethasone, or control prior to and during the HDM challenges as shown (A). Control nonsensitized mice received SAL. Mice were also treated with antagomirs (ant-miR) intranasally (50 μg/50 μL saline) or scrambled control (ant-scrambled) or dexamethasone (3 mg/kg) or vehicle control intraperitoneally (A). miRNA-specific qPCR for miR-145, (B) miR-21, (C) and let-7b (D) was conducted on RNA isolated from the airways and normalized to the expression of ribosomal RNA 18S. Data are expressed as fold change from expression levels of SAL controls ± SEM (n = 4-8). ∗P ≤ .05. D, Day; I.N., intranasal; I.P., intraperitoneal. Journal of Allergy and Clinical Immunology 2011 128, 160-167.e4DOI: (10.1016/j.jaci.2011.04.005) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Inhibition of miR-145 function by antagomir reduced inflammation in the airways in a manner comparable to dexamethasone treatment. Paraffin-embedded airway tissues from mice treated with specific antagomirs (ant-miR), scrambled control sequence (ant-scrambled), dexamethasone (DEX), or vehicle control (veh) were stained with periodic acid-Schiff (PAS) or Congo Red (CR) for the detection of mucus-producing cells (A-C) or peribronchial eosinophils (D-F), respectively. Cells were identified morphologically and enumerated from 10 high-power fields (HPFs) at ×1000 magnification. G, Representative photographs of cells stained for mucus expression (PAS) and eosinophil infiltrates (CR) in each group with amplified sections showing eosinophil morphology. Results are mean ± SEM (n = 4-8). ∗P ≤ .05. Journal of Allergy and Clinical Immunology 2011 128, 160-167.e4DOI: (10.1016/j.jaci.2011.04.005) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Inhibition of miR-145 function by antagomir reduced AHR in a magnitude comparable to dexamethasone treatment. A-C, Lung resistance is presented as a percentage change over baseline measurement (SAL) in response to inhaled methacholine. Mice were treated with specific antagomirs (ant-miR), scrambled control sequence (ant-scrambled), or dexamethasone (DEX) or vehicle control (veh). Resistance (RI) results are mean ± SEM (n = 6-10). ∗P ≤ .05 between dose response curves. Journal of Allergy and Clinical Immunology 2011 128, 160-167.e4DOI: (10.1016/j.jaci.2011.04.005) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Inhibition of miR-145 function by antagomir reduced inflammatory cytokine production within the draining lymph nodes to a level comparable to dexamethasone treatment (A-C). Peribronchial lymph nodes of the lung were collected from mice treated with specific antagomirs (ant-miR), scrambled control sequence (ant-scrambled) (A and C), dexamethasone (Dex), or vehicle control (veh) (B). Cells were cultured for 6 days before to supernatant collection. ELISA was conducted for IL-5, IL-13, and IFN-γ, and levels are shown from in vitro HDM-stimulated peribronchial lymph node supernatants above unstimulated levels. Cytokine-specific qPCR was preformed in whole lung lysates and is shown for allergic mice treated with antagomirs (D) or dexamethasone (E). Results are mean ± SEM (n = 6-10). ∗P ≤ .05. Journal of Allergy and Clinical Immunology 2011 128, 160-167.e4DOI: (10.1016/j.jaci.2011.04.005) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 miRNA-specific qPCR for miR-145 was conducted on RNA isolated from the airways and normalized to the expression of ribosomal RNA 18s. Data are expressed as mean fold change from expression levels of SAL controls ± SEM (n = 4-8). P ≤ .05. Journal of Allergy and Clinical Immunology 2011 128, 160-167.e4DOI: (10.1016/j.jaci.2011.04.005) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Total number of cells in bronchoalveolar lavage fluid of allergic house dust mite sensitized and challenged mice treated with specific antagomir 145 (ant–miR-145), scrambled control sequence (ant-scrambled), no treatment (HDM) and nonallergic saline controls (SAL; A) or dexamethasone (Dex) or vehicle control (Veh; B). ∗P ≤ .05. Journal of Allergy and Clinical Immunology 2011 128, 160-167.e4DOI: (10.1016/j.jaci.2011.04.005) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Both antagomir targeting miR-145 and dexamethasone display limited ability to reverse established allergic inflammation within the lung. Lung sections from mice treated with a single dose of antagomir targeting miR-145 (HDM + ant–miR-145), scrambled control sequence (HDM–ant-scrambled), dexamethasone (HDM + DEX), or vehicle control (Veh) were stained with periodic acid-Schiff (PAS) or Congo Red (CR) for the detection of mucus-producing cells (A) or peribronchial eosinophils (B), respectively. Cells were identified morphologically and enumerated from 10 high-power fields (HPFs) at ×1000 magnification. C, Lung resistance (RI) is presented as a percentage change over baseline measurement (SAL) in response to inhaled methacholine. Results are mean ± SEM (n = 6). ∗P ≤ .05. Journal of Allergy and Clinical Immunology 2011 128, 160-167.e4DOI: (10.1016/j.jaci.2011.04.005) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions