Targeting the IL-33/ST2 pathway in asthma : implications for development, exacerbation and treatment

Asthma is a term that encompasses a disease spectrum with different phenotypes that vary in severity and whose common characteristic is airflow limitation. Allergic asthma is the most common phenotype of asthma and is characterized by allergen induced inflammatory responses, airway hyperresponsiveness (AHR), and remodeling. The limitations of current treatment together with the prospect of curative therapies set the incentive for identifying novel targets for asthma treatment. The epithelium-derived cytokine interleukin-33 (IL-33) and its receptor ST2 are implicated in the initiation and progression of asthma by several genetic and experimental studies. This thesis investigates the role of the IL-33/ST2 pathway in asthma development, exacerbation and treatment, using mouse models of asthma. In paper I, we investigated the role of IL-33/ST2 signaling in promoting allergen-induced AHR, airway inflammation, and remodeling in a mouse model of asthma, in which wild-type and ST2 mice were exposed to intranasal instillations of house dust mite (HDM) extract. We revealed that ST2-dependent signaling is important for the development of AHR in the peripheral lung compartment and for the development of inflammatory responses including airway eosinophilia, induction of allergen-specific IgE, inflammation and goblet cell hyperplasia in the peripheral airways, and production of the cytokines IL-5, IL-13 and IL-33. In paper II, we tested the hypothesis that IL-33/ST2-dependent mast cell responses contribute to the development of AHR and airway inflammation, using a model where the lungs of mast cell deficient mice were engrafted with either wild-type or ST2 bone marrow derived mast cells, and subsequently exposed to HDM. Unexpectedly, we discovered a protective role for ST2-dependent mast cell responses in the development of AHR located in the peripheral lung. This protective effect appeared to be independent of airway inflammation but was associated with elevated levels of PGE2, which has a bronchoprotective role in asthma. In paper III, we explored the potential of IL-33 to exacerbate allergen-induced asthma responses by exposing OVA-sensitized mice to IL-33 before each antigen challenge. We found that IL-33 acted cooperatively with antigen to aggravate AHR, remodeling and several inflammatory responses, including a substantial potentiation of antigen-specific IgE antibody production, increased mast cell activity, elevated levels of the TH2 cytokines IL-4, IL-5 and IL13, and accumulation of inflammatory cells in the airways and lung tissue, including expansion of the ILC2 population in the lungs. In paper IV, we evaluated the effects of vaccination against IL-33 in a mouse model of HDM-induced asthma. The vaccine comprised a recombinant IL-33 protein modified to induce immunological memory response, while reducing its cytokine activity. Vaccination against IL33 induced high titers of anti-IL-33 IgG antibodies, and attenuated several HDM-induced responses including AHR, airway eosinophilia, accumulation of inflammatory cells in the airways, and the levels of inflammatory cytokines including IL-25, IL-33 and TSLP. In conclusion, the work presented in this thesis provides further evidence and new insights into the importance of the IL-33/ST2 pathway in the development of asthma. The studies of this thesis identify an important role for this pathway in the regulation of AHR in the peripheral lung compartment, a protective role on AHR mediated by mast cells, and a role in asthma exacerbations associated with the expansion of the ILC2 population. Finally, we demonstrate that targeting the IL-33/ST2 pathway by vaccination against IL-33 has the potential to be an effective therapeutic tool for treating asthma. LIST OF SCIENTIFIC PAPERS I. Anna Zoltowska, Ying Lei, Barbara Fuchs, Carola Rask, Mikael Adner and Gunnar Nilsson The interleukin-33 receptor ST2 is important for the development of peripheral airway hyperresponsiveness and inflammation in a house dust mite mouse model of asthma. Clinical & Experimental Allergy 2015; 46, 479-490 II. Anna Zoltowska Nilsson, Ying Lei, Mikael Adner and Gunnar Nilsson Mast cell dependent IL-33/ST2 signaling is protective against the development of airway hyperresponsiveness in a house dust mite mouse model of asthma Manuscript III. Lisa Sjöberg*, Anna Zoltowska Nilsson*, Ying Lei, Joshua Gregory, Mikael Adner and Gunnar Nilsson Interleukin 33 exacerbates antigen driven airway hyperresponsiveness, inflammation and remodeling in a mouse model of asthma Accepted Scientific Reports 2017 *These authors contributed equally IV. Ying Lei, Vamsi Boinapally*, Anna Zoltowska*, Mikael Adner, Lars Hellman and Gunnar Nilsson. Vaccination against IL-33 Inhibits Airway Hyperresponsiveness and Inflammation in a House Dust Mite Model of Asthma PLoS One. 2015; 10(7): e0133774 *These authors contributed equally Publications not included in this thesis Saluja R, Zoltowska A, Ketelaar ME, Nilsson G. IL-33 and Thymic Stromal Lymphopoietin in mast cell functions Eur J Pharmacol. 2016 May 5;778:68-76 Suttle MM, Enoksson M, Zoltowska A, Chatterjee M, Nilsson G, Harvima IT. Experimentally induced psoriatic lesions associate with rapid but transient decrease in interleukin-33 immunostaining in epidermis Acta Derm Venereol. 2015 May;95(5):536-41 Nilsson OB, Binnmyr J, Zoltowska A, Saarne T, van Hage M, Grönlund H. Characterization of the dog lipocalin allergen Can f 6: the role in cross-reactivity with cat and horse Allergy. 2012 Jun;67(6):751-7