Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.622030
Title: The role of interleukin-33 in mucosal inflammation and fibrosis
Author: Li, Dong
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2014
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Abstract:
Background: Interleukin (IL)-33 is a newly identified member of the IL-1 cytokine family. Multiple cell types are able to produce or respond to IL-33, including non-haematopoietic structural cells, innate and adaptive immune cells. The biological activity of IL-33 was initially described as being associated with the promotion of type 2 immune responses which were characterized by the induction of CD4+ T helper (Th) 2 cells. For example, exogenous administration of IL-33 in experimental models caused pathological changes in mucosal tissues such as the lung and gastrointestinal tracts; early studies reported that IL-33 can activate Th2 cells, mast cells, eosinophils or basophils to produce type 2 cytokines such as IL-4, IL-5, and IL-13. This was associated with pathological changes reminiscent of asthma, fibrosis and ulcerative colitis. Recently, a newly recognised cell population which was inducible by IL-33 and referred to as ‘type 2 innate lymphoid cells’ was identified and these were thought to be important for initiating type 2 immunity. However, the underlying mechanism by which IL-33 was involved in the inflammation and remodelling of diseases of the respiratory and gastrointestinal tracts remains to be fully understood. Hypothesis: My hypothesis is that IL-33 is induced in the gut and lung mucosa by inflammatory signals and mediates both early inflammation and late fibrosis by amplifying the innate immune response. Aims: To address this hypothesis I set out the following aims: i) to investigate the induction and effect of IL-33 via its receptor ST2 on cellular pathogenic pathways in the development of lung fibrosis (chapter 3); ii) to unravel the mechanism by which IL-33 promotes lung fibrosis (chapter 4); iii) to understand the involvement of the IL-33/ST2 pathway in ulcerative colitis (chapter 5). Methods: To address these aims I used two experimental murine models. To investigate the effect of IL-33 in the fibrosis phase of airway mucosal inflammation I used the bleomycin (BLM)-induced lung fibrosis (chapters 3 and 4). To investigate the effect of IL-33 in the acute phase of mucosal inflammation in the gut, I used dextran sulphate sodium (DSS)-induced colitis (chapter 5). These disease models are widely accepted for laboratory investigation and I acknowledge that they do not reflect the full complexity of the human conditions. However they are extremely useful for hypothesis generation. Results: My results showed i) that IL-33 promotes the pathogenesis of bleomycin-induced lung fibrosis. This was indicated by IL-33 being constitutively expressed in lung epithelial cells but induced in macrophages by bleomycin. The specificity of this response was confirmed by using either ST2-deficient mice, or neutralising anti-IL-33 antibody treatment, which both attenuated lung fibrosis (chapter 3). ii) that IL-33 promotes the initiation and progression of pulmonary fibrosis by recruiting and directing inflammatory cell function, and enhancing the production of pro-fibrogenic cytokines IL-13 and TGF-β in an ILC2- and M2-macrophages (chapter 4). iii) that IL-33 signalling via ST2 induces an IL-4-dependent immune response that is pathogenic in the early stage of ulcerative colitis. I found that the clinical indices of DSS-induced experimental UC, diarrhoea and colon inflammation, were respectively impaired in ST2 knockout mice and exacerbated in WT mice by treatment with exogenous recombinant IL-33. These were associated respectively with reduced and enhanced expression of inflammatory chemokines and angiogenic cytokines in vivo. The exacerbation effect of treatment with recombinant IL-33 on DSS-induced acute colitis was abolished in IL-4 knockout mice (chapter 5). Conclusion and prospect: Together, my results demonstrated that IL-33 expression was up-regulated in the lung and colon epithelium/endothelium in experimental BLM-induced fibrosis and DSS-induced colitis respectively. Furthermore, IL-33 exacerbated both diseases through recruiting and activating inflammatory cells and increasing the production of type 2 cytokines. Finally, I discussed the pathological mechanisms of IL-33 in mucosal tissue based on my results and the current literature. I concluded that this insight into IL-33 biology is informative of a new potential pathogenic pathway and might be a useful biomarker of disease and that targeting IL-33 may provide a new biological therapeutic approach in these disorders (chapter 6).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.622030  DOI: Not available
Keywords: QR180 Immunology
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