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ST2 & TLRs: coordination of chemokine-driven immunity

Moore, Mark (2009) ST2 & TLRs: coordination of chemokine-driven immunity. PhD thesis, University of Glasgow.

Due to Embargo and/or Third Party Copyright restrictions, this thesis is not available in this service.

Abstract

Abstract The detection of pathogen-associated molecules by Toll-like receptors (TLRs) is instrumental to the induction and regulation of an inflammatory response. However, prolonged or inappropriate stimulation of TLRs is associated with disease. A family of molecules coded for by the ST2 gene have been implicated as negative regulators of TLR4-signalling in murine cells. Here, the existence and potential role of these ST2 molecules in human macrophages has been investigated. Following the discovery of IL-33 as a ligand for ST2, the effect of this ligand on human macrophages was explored. We found elevated levels of the soluble form of ST2 (sST2) in the synovial fluid (SF) of patients with inflammatory forms of arthritis compared to amount in SF from people diagnosed with a less inflammatory form of arthritis. First confirming that human macrophages express the trans-membrane version of ST2 known as ST2L, we showed these cells respond to a recombinant form of the IL-33 ligand by inducing the release of inflammatory chemokines but not cytokines. The migration of inflammatory cells into inflamed tissue is influenced by their recognition of chemokines. The expression of receptors for these chemokines, the so called chemokine receptors (CCRs) is therefore pivotal in the recruitment of leukocytes into inflamed tissues. The regulation of the CCRs by TLR agonists has recently emerged as a fundamental axis in regulating inflammation. Whilst the local administration of TLR-ligands paradoxically increases leukocyte recruitment to sites of inflammation (thereby exacerbating it), in contrast, low, systemic doses of TLR-ligand have been found to be anti-inflammatory. The work of the second part of this thesis has reinforced the concept that the attenuation of inflammation by systemically-delivered TLR-agonists is due to a reduced migration of leukocytes into sites of inflammation. By adoptively transferring an equal number of discretely labelled cells from WT- and TLR2-KO- mice into WT mice with an existing inflammation, we were able to show that systemic administration of a TLR2 agonist caused a reduction in the number of transferred WT- but not TLR2-KO- cells migrating into the site inflammation. Consistent with this, more WT- than TLR2-KO-cells were detected in the lymph nodes of TLR2 agonist-, but not control- treated mice. For the first time the anti-inflammatory effect of TLR ligands has been shown to work in a cell autonomous manner, i.e. the migratory cells need to detect the TLR ligand directly for their migratory capacity to be diminished.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Due to copyright restrictions the full text of this thesis cannot be made available online. Access to the printed version is available.
Subjects: R Medicine > R Medicine (General)
Q Science > Q Science (General)
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Supervisor's Name: McInnes, Prof. Iain
Date of Award: 2009
Depositing User: Dr Mark Moore
Unique ID: glathesis:2009-830
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 04 Jun 2009
Last Modified: 10 Dec 2012 13:26
URI: http://theses.gla.ac.uk/id/eprint/830

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