IL-33 drives influenza-induced asthma exacerbations by halting innate and adaptive antiviral immunity

• Published in: Journal of allergy and clinical immunology Vol. 143; no. 4; pp. 1355 - 1370.e16
• Main Authors: Ravanetti, Lara, Dijkhuis, Annemiek, Dekker, Tamara, Sabogal Pineros, Yanaika S., Ravi, Abilash, Dierdorp, Barbara S., Erjefält, Jonas S., Mori, Michiko, Pavlidis, Stelios, Adcock, Ian M., Rao, Navin L., Lutter, René
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2019; Elsevier Limited
• Subjects: Adaptive Immunity - immunology; airway hyperresponsiveness; airways epithelial cells; Alveoli; Animals; Antiviral activity; Antiviral drugs; Asthma; Asthma - immunology; Asthma - virology; Automation; Clinical Medicine; Cytokines; Dendritic cells; Dust; Epithelial cells; exacerbation; Flow cytometry; Gene expression; Humans; IL-33; Immune response; Immunity; Immunity, Innate - immunology; Immunopathogenesis; Influenza; Influenza A Virus, H3N2 Subtype; Influenza, Human - complications; Influenza, Human - immunology; Interleukin-33 - immunology; Klinisk medicin; Laboratory animals; Lungmedicin och allergi; Lymphocytes T; Medical and Health Sciences; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; NETosis; Orthomyxoviridae Infections - immunology; Phenotypes; Pneumonia - immunology; Pneumonia - virology; Proteins; Respiratory function; Respiratory Medicine and Allergy; Respiratory syncytial virus; Respiratory tract; Respiratory tract diseases; Rhinovirus; Software; Symptom Flare Up; Thymic stromal lymphopoietin; Thymus; β-Interferon; influenza; OX40L; AHR; TCID50; MPO; RV16; HDM; ILC2; ILC3; moDC; dendritic cells; immune response; FDR; KC; qPCR; EC; iNKT; LTi; airway hyperresponsiveness; cDC; airways epithelial cells; TSLP; IL-33; BAL; mLN; Asthma; exacerbation; NETosis; MIP; PBEC; NCR; NET; FC; NK; DC
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2018.08.051

Influenza virus triggers severe asthma exacerbations for which no adequate treatment is available. It is known that IL-33 levels correlate with exacerbation severity, but its role in the immunopathogenesis of exacerbations has remained elusive. We hypothesized that IL-33 is necessary to drive asthma exacerbations. We intervened with the IL-33 cascade and sought to dissect its role, also in synergy with thymic stromal lymphopoietin (TSLP), in airway inflammation, antiviral activity, and lung function. We aimed to unveil the major source of IL-33 in the airways and IL-33–dependent mechanisms that underlie severe asthma exacerbations. Patients with mild asthma were experimentally infected with rhinovirus. Mice were chronically exposed to house dust mite extract and then infected with influenza to resemble key features of exacerbations in human subjects. Interventions included the anti–IL-33 receptor ST2, anti–TSLP, or both. We identified bronchial ciliated cells and type II alveolar cells as a major local source of IL-33 during virus-driven exacerbation in human subjects and mice, respectively. By blocking ST2, we demonstrated that IL-33 and not TSLP was necessary to drive exacerbations. IL-33 enhanced airway hyperresponsiveness and airway inflammation by suppressing innate and adaptive antiviral responses and by instructing epithelial cells and dendritic cells of house dust mite–sensitized mice to dampen IFN-β expression and prevent the TH1-promoting dendritic cell phenotype. IL-33 also boosted luminal NETosis and halted cytolytic antiviral activities but did not affect the TH2 response. Interventions targeting the IL-33/ST2 axis could prove an effective acute short-term therapy for virus-induced asthma exacerbations. [Display omitted]