IL-33 and ST2 in innate and adaptive airway inflammation

Murphy, Grace E. J. (2015) IL-33 and ST2 in innate and adaptive airway inflammation. PhD thesis, University of Glasgow.

Abstract

Background: ST2 has been identified in playing an important role in Th2-mediated inflammation and asthma. IL-33 acts as the ligand for ST2; it is a novel cytokine that induces innate Th2/type-2 responses when delivered to the lung. The hierarchy of IL-33 and type-2 cytokines and chemokines in Th2 inflammation in the lung has not been fully elucidated. Furthermore, the role of IL-33 in the adaptive response in allergic mediated airways disease is unclear.
Epithelial cells (ECs) are increasingly recognised as having an immunological role in airway inflammation and asthma, in particular releasing cytokines such as IL-33. Little is known about whether ST2 is expressed on these cells and what function IL-33 responsive ECs may have in Th2 diseases.
Soluble ST2 (sST2) has emerged as a biomarker correlating with disease activity in cardiovascular disease. It is not known if there is a clear association between sST2 and asthma, nor whether measurable IL-33 concentrations are present and if so, their association with disease severity. The influence of smoking and corticosteroid treatment on these parameters has also not been determined.
Aim: To ascertain the levels of systemic sST2 and IL-33 in asthmatic patients. To determine cytokine, chemokine and airway dynamics of IL-33-driven innate airway inflammation. To determine the role of epithelial cells in IL-33-driven innate airway inflammation. To investigate the function of ST2/IL-33 axis in the innate and adaptive responses in allergic airways inflammation and asthma.
Methods and Results: sST2 and IL-33 levels in plasma of never smokers, ex-smokers and smokers were determined by immunoassay before and after a corticosteroid trial. Corticosteroid treatment resulted in increased sST2 levels in all smoking status patient groups; there was no effect attributable to smoking.
Time course and dosage interval experiments were performed in mice treated with intranasal IL-33. IL-5, IL-13, eotaxin/CCL11 and eotaxin2/CCL24 mediated eosinophilic airway inflammation (AI). Treatment of mice with both anti- CCL11 and -CCL24 partially ameliorated the AI. IL-4 gene deficient mice were protected from IL-33-induced inflammation. BALB/c mice displayed airways hyperreactivity following IL-33 treatment.
Murine, human cell line and primary human ECs were assessed for ST2 expression by immunohistochemistry and fluorescence activated cell sorting (FACS). ST2 expression was clearly demonstrated in the ECs. Subsequently ECs were treated with IL-33 in an in vitro setting including in a pseudostratifed epithelium model. ECs produced a range of inflammatory and angiogenic mediators in response to IL-33. In particular IL-33 driven EC-derived VEGF promoted angiogenesis in vitro. Intranasal IL-33 induced increased endothelial cells and vascular remodelling in vivo.
Experimental allergic airways inflammation (AAI) was generated in BALB/c mice which were co-treated with IL-33 or PBS at allergen sensitisation. IL-33 induced the polarisation of IL-5+IL-4- T cells in the draining lymph nodes and these mice developed more severe inflammation.
AAI was induced in WT, ST2-deficient, IL-4-deficient and ST2/IL-4 deficient mice. These experiments showed IL-4 was necessary for generation of AAI which could not be overcome by ST2-pathway stimulation in an adjuvant-free model.
Conclusions: The data presented further extends the current understanding of the ST2/IL-33 axis in the innate and adaptive aspects of Th2 inflammation in AAI and asthma. In particular the hierarchy of mediators and cells involved in Th2 inflammation, including at the sensitisation phase, have been explored. This identifies ST2/IL-33 as a potential target in the development of biological therapies for asthma.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: IL-33, ST2, asthma, allergy, Th2, epithelial cell
• Subjects: Q Science > QR Microbiology > QR180 Immunology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Immunology & Infection
• Supervisor's Name: Liew, Professor Foo and Thomson, Professor Neil C.
• Date of Award: 2015
• Depositing User: Dr Grace Murphy
• Unique ID: glathesis:2015-6685
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 08 Oct 2015 11:17
• Last Modified: 09 Oct 2015 14:18
• URI: https://theses.gla.ac.uk/id/eprint/6685