title: A novel small molecule TLR4 antagonist (IAXO-102) negatively regulates non-hematopoietic toll like receptor 4 signalling and inhibits aortic aneurysms development.
abstract: OBJECTIVE
  The toll-like receptors (TLRs), including TLR4, have been shown to play a crucial role in vascular inflammatory diseases, such as atherosclerosis and aneurysm. The main goal of this study was to determine the potential of IAXO-102 (Innaxon, Tewkesbury), a novel small molecule TLR4 antagonist, to modulate non-hematopoietic TLR4 proinflammatory signalling and inhibit experimental abdominal aortic aneurysm (AAA) development.
  
  
  METHODS
  Human umbilical vein endothelial cells (HUVEC) and Angiotensin II-induced experimental AAA development were our in vitro and in vivo models respectively. Western blotting, antibody array and ELISA approaches were used to explore the effect of IAXO-102 on TLR4 functional activity on two levels: modulation of TLR4-induced mitogen activated protein kinases (MAPK) and p65 NF-kB phosphorylation and expression of TLR4 dependent proinflammatory proteins.
  
  
  RESULTS
  Following activation of TLR4, in vitro/in vivo data revealed that IAXO-102 inhibited MAPK and p65 NF-kB phosphorylation associated with down regulation of the expression of TLR4 and TLR4 dependent proinflammatory proteins. Furthermore, IAXO-102 decreased Angiotensin II-induced aortic expansion, rupture and incidence of AAA.
  
  
  CONCLUSIONS
  These results demonstrate the ability of IAXO-102 to negatively regulate TLR4 signalling and to inhibit experimental AAA development, suggesting the potential therapeutic use of this TLR4 antagonist for pharmacological intervention of AAA.
authors: Institute of Cardiovascular Sciences and Cell Biology, St Georges University of London, UK.
authors: Christopher
authors: C
authors: Huggins
authors: Institute of Cardiovascular Sciences and Cell Biology, St Georges University of London, UK.
authors: Stuart
authors: S
authors: Pearce
authors: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Italy.
authors: Francesco
authors: F
authors: Peri
authors: Innaxon, Tewkesbury, UK.
authors: Frank
authors: F
authors: Neumann
authors: Institute of Cardiovascular Sciences and Cell Biology, St Georges University of London, UK.
authors: Gillian
authors: G
authors: Cockerill
authors: Department of Biomedical and Forensic Sciences, Anglia Ruskin University, Cambridge, UK. Electronic address: grisha.pirianov@anglia.ac.uk.
authors: Grisha
authors: G
authors: Pirianov
mesh_terms: D000606:Amino Sugars / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000378:metabolism*; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy* / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D006017:Glycolipids / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D015994:Incidence; D007249:Inflammation; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D000606:Amino Sugars; D001057:Apolipoproteins E; D006017:Glycolipids; C000609572:IAXO-102; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA
keywords: Experimental aneurysms; Toll like receptor 4; Toll like receptor 4 antagonist IAXO-102; Vascular inflammation