Death Receptor 3 (DR3) is a death domain containing member of the TNF Receptor Superfamily (TNFRSF), refereeing a range of cellular responses from differentiation and proliferation to cell death, depending upon the context of receptor activation. DR3 has been reported to have a role in many inflammatory diseases, including inflammatory arthritis and inflammatory bowel disease. The aim of this study was to determine the contribution of DR3 in a mouse model of acute and chronic allergic lung inflammation. Mice genetically deficient in the DR3 gene (DR3ko) were resistant to cellular accumulation within the lungs and bronchoalveolar lavage following acute lung inflammation, induced by priming with ovalbumin (OVA) and the adjuvant aluminium hydroxide (Alum) prior to 2 OVA aerosol exposures. To discern the role of DR3 in a more physiologically relevant chronic model of allergic lung inflammation, mice underwent repeated inhalation challenges with OVA subsequent to priming with OVA and Alum. Whilst cellular accumulation did not differ, DR3ko mice displayed reduced immuno-histopathology, and goblet cell hyperplasia, hallmarks of the asthmatic phenotype. Intriguingly, DR3ko mice exhibited reduced accumulation of various cell types into the spleen in both models. Early priming events were therefore investigated, prior to aerosolised antigenic challenge to decipher the effects of DR3. One sensitisation injection was sufficient to induce decreased DR3ko splenocyte accumulation, though T and B cell responses were observed to be comparable between DR3ko and DR3wt controls. DR3ko mice had depleted CXCL10 levels, suggesting cellular recruitment in response to inflammation is DR3 dependent. The underlying DR3 dependent mechanisms concerning the DR3ko splenic defects are under further investigation and may have impact on the use of the DR3/TL1A pathway as a therapeutic target, either as an anti-inflammatory or as a booster of the immune response to pathogens.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:590378 |
| Date | January 2014 |
| Creators | Singh, Ravinder |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/56963/ |
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