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IL-33 Drives Influenza-Induced Exacerbations of Asthma and Halts Innate and Adaptive Anti-Viral Responses by Instruction of Epithelial and Dendritic Cells
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A6225 - IL-33 Drives Influenza-Induced Exacerbations of Asthma and Halts Innate and Adaptive Anti-Viral Responses by Instruction of Epithelial and Dendritic Cells
Author Block: L. Ravanetti1, A. Dikhuis2, Y. S. Sabogal Piñeros2, R. Lutter1, U-BIOPRED Study Group; 1Respiratory Medicine, Academic Medical Centre/University of Amsterdam, Amsterdam, Netherlands, 2Experimental Immunology, Academic Medical Centre/University of Amsterdam, Amsterdam, Netherlands.
Introduction: Influenza virus triggers severe exacerbations of asthma for which no adequate treatment is available. It is known that IL-33 levels correlate with exacerbation severity, but its role in the immune-pathogenesis of exacerbations has remained elusive. We hypothesized that IL-33 is necessary to drive asthma exacerbations. Aim: By blocking the IL-33 receptor (ST2) we intervened with the IL-33 cascade to dissect its role in airway inflammation, anti-viral activity and lung function. Methods: Mice sensitized (i.n.) to HDM extract or not (NaCl controls), were infected with influenza A/X31 (HDM/X31; NaCl/X31) (Ravanetti et al. Allergy 2016); 3 days before and after the infection mice were treated (i.p.) with mAbs directed against ST2 (αST2) or the isotype control. 14 hours, 1, 2, 4, 6, 8 days post-infection, the inflammatory infiltrate was assessed in bronchoalveolar lavage fluid (BALF), lung and draining lymph nodes (mLNs); cytokines were measured in BALF and lung; airway hyperresponiveness (AHR) and lung viral load were determined. Results: Blocking ST2 in HDM/X31 and NaCl/X31 mice significantly attenuated AHR and viral replication (day 7 and 8, respectively), markedly reduced eosinophils, neutrophils, DCs, macrophages, B and T (CD4+) cells, ILC2 in BALF (over time), in lung (14 hours post-infection) and in mLNs (with biphasic kinetics on day 1 and 6 post-infection) compared to isotype controls. Furthermore, by blocking ST2 unveiled that IL-33 suppressed Th1-like, innate anti-viral responses without affecting Th2-like responses and promoted NETosis during asthma exacerbation. IL-33 instructed airway epithelial cells and DC to dampen IFN-β expression and prevent the Th-1-promoting DC phenotype. Therefore blocking IL-33 could prove a novel acute therapy in course of virus-induced asthma exacerbation. Conclusion: Blocking IL33 could prove a novel acute therapy in course of virus-induced asthma exacerbation. The study is supported by U-BIOPRED consortium that receives funding from the European Community and from the European Federation of Pharmaceutical Industries and Associations as an IMI JU funded project and by Chiesi Farmaceutici S.p.A.
Author Block: L. Ravanetti1, A. Dikhuis2, Y. S. Sabogal Piñeros2, R. Lutter1, U-BIOPRED Study Group; 1Respiratory Medicine, Academic Medical Centre/University of Amsterdam, Amsterdam, Netherlands, 2Experimental Immunology, Academic Medical Centre/University of Amsterdam, Amsterdam, Netherlands.
Introduction: Influenza virus triggers severe exacerbations of asthma for which no adequate treatment is available. It is known that IL-33 levels correlate with exacerbation severity, but its role in the immune-pathogenesis of exacerbations has remained elusive. We hypothesized that IL-33 is necessary to drive asthma exacerbations. Aim: By blocking the IL-33 receptor (ST2) we intervened with the IL-33 cascade to dissect its role in airway inflammation, anti-viral activity and lung function. Methods: Mice sensitized (i.n.) to HDM extract or not (NaCl controls), were infected with influenza A/X31 (HDM/X31; NaCl/X31) (Ravanetti et al. Allergy 2016); 3 days before and after the infection mice were treated (i.p.) with mAbs directed against ST2 (αST2) or the isotype control. 14 hours, 1, 2, 4, 6, 8 days post-infection, the inflammatory infiltrate was assessed in bronchoalveolar lavage fluid (BALF), lung and draining lymph nodes (mLNs); cytokines were measured in BALF and lung; airway hyperresponiveness (AHR) and lung viral load were determined. Results: Blocking ST2 in HDM/X31 and NaCl/X31 mice significantly attenuated AHR and viral replication (day 7 and 8, respectively), markedly reduced eosinophils, neutrophils, DCs, macrophages, B and T (CD4+) cells, ILC2 in BALF (over time), in lung (14 hours post-infection) and in mLNs (with biphasic kinetics on day 1 and 6 post-infection) compared to isotype controls. Furthermore, by blocking ST2 unveiled that IL-33 suppressed Th1-like, innate anti-viral responses without affecting Th2-like responses and promoted NETosis during asthma exacerbation. IL-33 instructed airway epithelial cells and DC to dampen IFN-β expression and prevent the Th-1-promoting DC phenotype. Therefore blocking IL-33 could prove a novel acute therapy in course of virus-induced asthma exacerbation. Conclusion: Blocking IL33 could prove a novel acute therapy in course of virus-induced asthma exacerbation. The study is supported by U-BIOPRED consortium that receives funding from the European Community and from the European Federation of Pharmaceutical Industries and Associations as an IMI JU funded project and by Chiesi Farmaceutici S.p.A.
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