Mechanisms of NOD1-induced inflammation in vascular tissue
Author(s)
Gatheral, Timothy
Type
Thesis
Abstract
Blood vessels play a vital role in human disease including pathogen driven conditions such as septic shock and acute lung injury. In the innate immune system, host pattern recognition receptors (PRRs) recognise preserved pathogen associated molecular patterns (PAMPs) leading to cell activation. Previous work has shown that blood vessels respond to Gram negative bacteria via the PRRs Toll like receptor 4 (TLR4) and nucleotide oligomerisation domain 1 (NOD1). Indeed stimulation with a specific NOD1 agonist can induce vascular shock in rats (Cartwright, Murch et al. 2007). In humans however, the role of NOD1 in blood vessels is relatively unexplored. Accordingly, in this thesis I have sought to characterise the activity of NOD1 in rodent and human vascular tissue with comparison to TLR4 responses.
I have shown that in rodents NOD1 is predominantly expressed and active in vascular cells and whole vessels. Crucially vessel organ culture suggests a predominant role for the endothelium in early responses to NOD1 and TLR4 agonists. I have then gone on to demonstrate induction of key inflammatory mediators by NOD1 agonists in human vessels and vascular cells, confirming the importance of the endothelium in this system. Finally I have used pharmacological tools to describe the signalling pathways downstream of NOD1 and TLR4 in endothelial cells including use of highly novel NOD1 pathway inhibitors.
In conclusion, NOD1 is identified as an important PRR mediating inflammatory responses in rodent and human vascular tissue. The endothelium emerges as a key site for NOD1 mediated inflammation whilst the use of highly novel signalling inhibitors has enabled clear differentiation of NOD1 and TLR4 signalling. This suggests the possibility of selective targeting of NOD1 in human disease where disorders of the vasculature predominate.
I have shown that in rodents NOD1 is predominantly expressed and active in vascular cells and whole vessels. Crucially vessel organ culture suggests a predominant role for the endothelium in early responses to NOD1 and TLR4 agonists. I have then gone on to demonstrate induction of key inflammatory mediators by NOD1 agonists in human vessels and vascular cells, confirming the importance of the endothelium in this system. Finally I have used pharmacological tools to describe the signalling pathways downstream of NOD1 and TLR4 in endothelial cells including use of highly novel NOD1 pathway inhibitors.
In conclusion, NOD1 is identified as an important PRR mediating inflammatory responses in rodent and human vascular tissue. The endothelium emerges as a key site for NOD1 mediated inflammation whilst the use of highly novel signalling inhibitors has enabled clear differentiation of NOD1 and TLR4 signalling. This suggests the possibility of selective targeting of NOD1 in human disease where disorders of the vasculature predominate.
Date Issued
2012-09
Date Awarded
2013-03
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Hansel, Trevor
Mitchell, jane
Sponsor
British Heart Foundation
Grant Number
FS/09/017/26810
Publisher Department
National Heart and Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)