Death Receptor 3 (DR3) is a death domain (DD) containing member of the Tumour Necrosis Factor Receptor Superfamily (TNFRSF) and has a single acknowledged TNFSF ligand called TNF-like protein 1A (TL1A). Previous research has implicated roles for DR3 in host immune defence and in various inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease (IBD), atherosclerosis and allergic lung inflammation. This thesis investigated a potential role for DR3 in co-ordinating the innate immune response, using an in vivo Staphylococcus epidermidis supernatant (SES) model of acute peritoneal inflammation. A further point of investigation looked at the effect of the absence of DR3 on thickening of the peritoneal membrane induced by repeated SES inflammation. My results showed that the DR3/TL1A pathway is not essential in maintaining the number of peritoneal or blood leukocytes during naive conditions. Stromal DR3 was found to be important in co-ordinating the innate immune response after the induction of acute SES induced inflammation, with significantly lower numbers of specific myeloid and lymphoid cell subsets accumulating in the peritoneal cavity of DR3 knockout (DR3-/-) mice. Despite this reduction in selected leukocyte numbers, the proportion of infiltrating cells exhibiting proliferation and cell death was unaffected by the absence of DR3. However reduced leukocyte numbers were associated with a significant reduction in the concentration of multiple chemoattractants in DR3-/- peritoneal supernatants compared to those from DR3+/+ mice. Quantitative RT-PCR data (qPCR) were consistent with the peritoneal membrane being a source of many of these chemoattractants. vi Results presented here identify for the first time a pro-inflammatory role for stromal DR3 in the innate immune response. However after repeatedly inducing inflammatory conditions DR3 promoted thickening of the peritoneal membrane, while an absence of DR3 prevented aberrant inflammation-induced tissue fibrosis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:577924 |
| Date | January 2013 |
| Creators | Perks, William Victor Thomas |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/50201/ |
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