The synovial environment in rheumatoid arthritis (RA) is a milieu of Damage Associated Molecular Patterns (DAMPs), cytokines and immune complexes, which can modulate the activation or polarisation of myeloid cells. GM-CSF, which is a pivotal myeloid cell growth factor, is also a pro-inflammatory cytokine that drives aspects of RA immunopathogenesis. Inhibition of GM-CSF signalling has been successful in both mouse models and in clinical trials for RA, however, the specific effect of GM-CSF on myeloid cells in a synovial setting is not well understood. The aim of this thesis was to investigate the impact of the synovial environment and GM-CSF on myeloid cells in RA. GM-CSF stimulation induced monocytes to secrete substantial amounts of the chemokine CCL17. However, this induction of CCL17 was significantly inhibitedupon co-stimulation with RA synovial fluid, but not osteoarthritis (OA) synovial fluid, whilst the expression of other chemokines was unaffected. TLR ligands also inhibited GM-CSF driven CCL17, however, through the use of MyD88/TRIF knockout mouse monocytes, we found RA synovial fluid inhibition of CCL17 was TLR-independent. Small Immune Complexes and IFNα also had the capacity to inhibit GM-CSF induction of CCL17, suggesting multiple mechanisms within the RA synovial fluid to prevent this induction. Despite the consistency of RA synovial fluid causing inhibition of the GM-CSF signalling pathway in comparison to OA synovial fluid, there were no distinct effects on macrophage polarisation. The RA synovial environment has more of an impact on monocyte activation in comparison to macrophage polarisation, as synovial fluid from other arthropathies had the comparable effects on macrophage phenotypes. This thesis concludes that RA synovial fluid contains several factors that inhibit GM-CSF induction of CCL17. This suggests a regulatory mechanism, preventing the excessive secretion of CCL17 by monocytes, thereby preventing exacerbation of immunopathogenesis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:705620 |
| Date | January 2017 |
| Creators | Kidger, Simone Verina |
| Publisher | University of Glasgow |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://theses.gla.ac.uk/8012/ |
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