The role of IL-33 and ST2 in innate and adaptive inflammation

Kewin, Peter (2007) The role of IL-33 and ST2 in innate and adaptive inflammation. PhD thesis, University of Glasgow.

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Inflammation is the body's response to injury and infection, and is aimed at eradicating the threat and repairing the tissue through the activation of the innate and adaptive immune systems. The innate inflammatory response is triggered by a surveillance network of broadly specific receptors. It is immediate and preprogrammed, and involves the activation of phagocytic cells and the release of soluble anti-microbial mediators to eradicate infection as quickly as possible. It can also promote the subsequent adaptive response. The adaptive inflammatory response is regulated by antigen-specific T helper (Th) lymphocytes, and has memory to provide immunity against repeat infection. These two arms of the immune system are often activated concurrently and communicate through the release of cytokines and chemokines to co-ordinate and regulate an appropriate response. Th cells differentiate into various effector cell types and co-ordinate different responses, often directing innate immune cells to carry out effector functions. Th1 cells produce IFNgamma and direct responses against intracellular pathogens through macrophage activation. Th2 cells produce IL-4, IL-5 and IL 13 and are important in resistance to parasites through mast cell and eosinophil activation. Th17 cells produce IL-17 and are important in sepsis through neutrophil activation. Dysregulation of these responses often contributes to the development of disease. Autoimmune diseases are characterised by Th1 and/or Th17 inflammation, whilst dysregulated Th2 responses result in allergy and asthma. Inflammatory diseases are often chronic and debilitating, and current therapies are either ineffective or have significant side effects, so novel inflammatory mechanisms and therapeutic targets are required. ST2L is a member of the IL-1 receptor family that was identified as a surface marker for Th2 cells, and is associated with Th2 cell activation and functions, although its precise role is unknown. IL 33 is a novel member of the IL-1 cytokine family, and has recently been identified as a ligand for ST2L. It promotes Th2 cytokine release and eosinophil accumulation in vivo. sST2 is a soluble form of ST2L that has broad immunosuppressive activity, although the mechanism is unknown. Therefore IL-33 and ST2 are potentially important inflammatory mediators, and in this thesis I aimed to demonstrate the role of IL-33 and ST2 in innate and adaptive inflammation, using murine models of allergic airways disease and autoimmune arthritis. I have shown that IL-33 administered directly to the airways provokes an innate Th2 type response in the lung with many characteristics in common with allergic airways disease. There was increased production of Th2 cytokines, except IL-4, chemokines and eosinophilic inflammation. ST2 gene knockout (ST2-/-) mice demonstrated this response was dependent on ST2, and SCID mice demonstrated that whilst non-lymphoid cells were sufficient to initiate a response, lymphoid cells enhanced it. IL-33 exacerbated the effector phase of Th2 allergic airways inflammation, with increased eosinophils, Th2 cytokines and chemokines in the airway, and increased lymph node responses. (ST2-/-) mice had reduced inflammation in the airway, despite normal lymph node responses, suggesting the role of IL-33 and ST2 is more important in the tissues. Pilot data also suggested that IL-33 exacerbates Th1/Th17 autoimmune collagen-induced arthritis (CIA), with increased disease severity and lymph node responses. ST2-/- mice had reduced disease severity, again despite normal lymph node responses. In summary, 1 have demonstrated that in the airway IL-33 is sufficient to induce a Th2 type innate response with pathological features similar to asthma. I have also shown that IL-33 can exacerbate Th2 mediated airway inflammation, and in addition, Th1/Th17 mediated arthritis. Thus it has general pro-inflammatory actions, and warrants further investigation to elucidate the mechanisms involved and fulfil its potential as a target for future therapeutic intervention.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Immunology, inflammation.
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: Xu, Dr. Damo
Date of Award: 2007
Depositing User: Enlighten Team
Unique ID: glathesis:2007-71136
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 May 2019 10:49
Last Modified: 07 Jul 2021 06:53
Thesis DOI: 10.5525/gla.thesis.71136

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