Dexamethasone induces ω3-derived immunoresolvents driving resolution of allergic airway inflammation Katerina Pyrillou, PhD, Aikaterini-Dimitra Chairakaki,

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Presentation transcript:

Dexamethasone induces ω3-derived immunoresolvents driving resolution of allergic airway inflammation Katerina Pyrillou, PhD, Aikaterini-Dimitra Chairakaki, PhD, Constantin Tamvakopoulos, PhD, Evangelos Andreakos, PhD Journal of Allergy and Clinical Immunology Volume 142, Issue 2, Pages 691-695.e4 (August 2018) DOI: 10.1016/j.jaci.2018.04.004 Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Effect of DXM on the biosynthesis of DHA-derived proresolving lipid mediators and the resolution of allergic airway inflammation. A, Schematic of the experimental protocol. DXM treatment is depicted in red. Rhombus indicates timepoints of collection. B, Tissue lipidomic profiling over a time course of 7 days postchallenge showing early activation of the DHA-17-HDHA-PD1/PDX pathway triggered by DXM. Data are expressed as fold induction relative to naive non-inflamed (N) mice. For levels below the limit of quantification (LOQ), half LOQ values were used.C, Total leukocyte, eosinophil, and lymphocyte numbers in BAL. D, TH2 cytokine responses in mediastinal lymph nodes. E, Resolution curves for total leukocyte and eosinophil numbers in BAL. F, Calculated resolution intervals (Ri) based on total leukocyte and eosinophil resolution curves. Data represent mean ± SEM of n = 9 to 23 mice/group pooled from at least 3 independent experiments. ***P < .001, **P < .01, and *P < .05 compared with PBS-treated controls. Journal of Allergy and Clinical Immunology 2018 142, 691-695.e4DOI: (10.1016/j.jaci.2018.04.004) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Dependence of DXM proresolving capacity on the activation of the DHA-17-HDHA-PD1/PDX pathway. A, Schematic of the experimental protocol using wild-type (WT) and Alox15-deficient (Alox15−/−) mice depicted in red. Rhombus indicates timepoints of collection. B, Tissue lipidomics analysis of non-treated Alox15−/− mice compared with WT mice. Data are expressed as fold induction relative to naive (N) mice. For levels below the limit of quantification (LOQ), half LOQ values were used. C, Effect of DXM administration on total leukocyte, eosinophil, and lymphocyte numbers in BAL at day 4 postchallenge. D, Effect of DXM administration on TH2-cell responses at day 4 postchallenge. Data represent mean ± SEM of n = 6 to 23 mice/group pooled from at least 3 independent experiments. ***P < .001, **P < .01, and *P < .05 compared with WT mice. Journal of Allergy and Clinical Immunology 2018 142, 691-695.e4DOI: (10.1016/j.jaci.2018.04.004) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Production of ω3-derived proresolving lipid mediators in the lung of mice with experimental allergic airway inflammation. A, Schematic of the experimental protocol. Naive (white), OVA-sensitized, PBS-challenged (gray), and OVA-sensitized, OVA-challenged (black) mice were studied. B, Total leukocyte and eosinophil presence in BAL. C, Edema formation assessed by wet-dry lung weight. D, TH2-cell responses in mediastinal lymph nodes. E, Induction of the DHA-17-HDHA-PD1/PDX pathway in the lung assessed by targeted lipidomics. F, Presence of the prostaglandins PGE2 and PGD2 in the lung assessed by targeted lipidomics. Data represent mean ± SEM of n = 5-43 mice/group pooled from at least 3 independent experiments. ***P < .001, **P < .01, and *P < .05 compared with naive mice. Journal of Allergy and Clinical Immunology 2018 142, 691-695.e4DOI: (10.1016/j.jaci.2018.04.004) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Production of ω3-derived proresolving lipid mediators in the serum of mice with experimental allergic airway inflammation. Naive (white), OVA- sensitized, PBS-challenged (gray), and OVA-sensitized, OVA-challenged (black) mice were studied. A, Quantification of DHA, its monohydroxy metabolites 7-HDHA and 17-HDHA, and EPA in mouse serum. No other DHA- or EPA-metabolites were identified. B, Presence of the arachidonic acid–derived prostaglandins PGE2 and PGD2 in mouse serum. Data represent mean ± SEM of n = 2-9 mice/group pooled from 2 independent experiments. Differences were not statistically significant when compared with naive mice. EPA, Eicosapentaenoic acid; 7-HDHA, 7-hydroxy-docosahexaenoic acid. Journal of Allergy and Clinical Immunology 2018 142, 691-695.e4DOI: (10.1016/j.jaci.2018.04.004) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 DXM accelerates resolution of airway inflammation. Monitoring of TH2 cytokine release at day 1 (A) and day 2 (B) post-DXM (red) administration compared with PBS-treated controls (black). Data represent mean ± SEM of n = 9 to 23 mice/group pooled from at least 3 independent experiments. *P < .05 compared with PBS-treated controls. Journal of Allergy and Clinical Immunology 2018 142, 691-695.e4DOI: (10.1016/j.jaci.2018.04.004) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions