Rahman, F.;
(2010)
An investigation of the macrophage-mediated acute inflammatory response in inflammatory bowel disease.
Doctoral thesis , UCL (University College London).
Abstract
Although the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC) remains poorly understood, increasing evidence implicates impaired innate immunity, orchestrated by macrophages, as the primary defect. In this thesis, the macrophage-mediated acute inflammatory response to microbial stimulation is characterised. Bacterial clearance, assessed in vivo using subcutaneous inoculation of 32P-labelled E. coli, was markedly impaired in CD. In vitro studies of macrophage function demonstrate grossly attenuated pro-inflammatory cytokine secretion, despite normal TLR signalling and cytokine mRNA levels and stability. The putative defect, based on differential macrophage gene expression, is a disordered secretory system causing aberrant post-translational cytokine processing, packaging and transport. Cytokine and gene expression profiles also identify ileal and colonic CD as distinct clinical entities. Conversely, the acute inflammatory response to bacterial challenge is exuberant and protracted in UC, despite normal bacterial clearance. In vitro macrophage studies identify a specific defect of the TLR4 TRIF-dependent signalling pathway, with over-expression of IFN-family related genes associated with T cell recruitment and activation. These novel studies considerably advance our understanding of the pathogenesis of IBD. Dysregulated macrophage-mediated innate immunity is a prominent feature in both CD and UC, although the molecular mechanisms underlying macrophage dysfunction differ in the two diseases. Counter-intuitively, both attenuated (CD) and exuberant (UC) acute inflammatory responses may eventuate in the T cell-mediated chronic inflammation characteristic of these diseases. Defining the precise underlying molecular defects may offer novel therapeutic targets in the future.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | An investigation of the macrophage-mediated acute inflammatory response in inflammatory bowel disease |
| Language: | English |
| Additional information: | Authorisation for digitisation not received |
| URI: | https://discovery.ucl.ac.uk/id/eprint/19807 |
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