title: A key role for the endothelium in NOD1 mediated vascular inflammation: comparison to TLR4 responses.
abstract: Understanding the mechanisms by which pathogens induce vascular inflammation and dysfunction may reveal novel therapeutic targets in sepsis and related conditions. The intracellular receptor NOD1 recognises peptidoglycan which features in the cell wall of gram negative and some gram positive bacteria. NOD1 engagement generates an inflammatory response via activation of NFκB and MAPK pathways. We have previously shown that stimulation of NOD1 directly activates blood vessels and causes experimental shock in vivo. In this study we have used an ex vivo vessel-organ culture model to characterise the relative contribution of the endothelium in the response of blood vessels to NOD1 agonists. In addition we present the novel finding that NOD1 directly activates human blood vessels. Using human cultured cells we confirm that endothelial cells respond more avidly to NOD1 agonists than vascular smooth muscle cells. Accordingly we have sought to pharmacologically differentiate NOD1 and TLR4 mediated signalling pathways in human endothelial cells, focussing on TAK1, NFκB and p38 MAPK. In addition we profile novel inhibitors of RIP2 and NOD1 itself, which specifically inhibit NOD1 ligand induced inflammatory signalling in the vasculature. This paper is the first to demonstrate activation of whole human artery by NOD1 stimulation and the relative importance of the endothelium in the sensing of NOD1 ligands by vessels. This data supports the potential utility of NOD1 and RIP2 as therapeutic targets in human disease where vascular inflammation is a clinical feature, such as in sepsis and septic shock.
authors.affiliation: Cardiothoracic Pharmacology, National Heart and Lung Institute, Imperial College, London, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Gatheral
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Reed
authors.forename: Laura
authors.initials: L
authors.lastname: Moreno
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gough
authors.forename: Bart J
authors.initials: BJ
authors.lastname: Votta
authors.forename: Clark A
authors.initials: CA
authors.lastname: Sehon
authors.forename: David J
authors.initials: DJ
authors.lastname: Rickard
authors.forename: John
authors.initials: J
authors.lastname: Bertin
authors.forename: Eric
authors.initials: E
authors.lastname: Lim
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Nicholson
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology; D006090:Gram-Negative Bacteria / Q000276:immunology / Q000378:metabolism; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000473:pathology; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D010457:Peptidoglycan / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology* / Q000378:metabolism; D014657:Vasculitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; D010457:Peptidoglycan; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C119067:NOD1 protein, human; C495345:TLR4 protein, human; C495347:Tlr4 protein, rat; C506253:RIPK2 protein, human