Christopher Huggins1, Stuart Pearce1, Francesco Peri2, Frank Neumann3, Gillian Cockerill1, Grisha Pirianov4. 1. Institute of Cardiovascular Sciences and Cell Biology, St Georges University of London, UK. 2. Department of Biotechnology and Biosciences, University of Milano-Bicocca, Italy. 3. Innaxon, Tewkesbury, UK. 4. Department of Biomedical and Forensic Sciences, Anglia Ruskin University, Cambridge, UK. Electronic address: grisha.pirianov@anglia.ac.uk.
Abstract
OBJECTIVES: 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.
OBJECTIVES: 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: Alison J Scott; Benjamin L Oyler; David R Goodlett; Robert K Ernst Journal: Biochim Biophys Acta Mol Cell Biol Lipids Date: 2017-01-17 Impact factor: 4.698
Authors: Steven J Forrester; George W Booz; Curt D Sigmund; Thomas M Coffman; Tatsuo Kawai; Victor Rizzo; Rosario Scalia; Satoru Eguchi Journal: Physiol Rev Date: 2018-07-01 Impact factor: 37.312
Authors: John K Hermann; Madhumitha Ravikumar; Andrew J Shoffstall; Evon S Ereifej; Kyle M Kovach; Jeremy Chang; Arielle Soffer; Chun Wong; Vishnupriya Srivastava; Patrick Smith; Grace Protasiewicz; Jingle Jiang; Stephen M Selkirk; Robert H Miller; Steven Sidik; Nicholas P Ziats; Dawn M Taylor; Jeffrey R Capadona Journal: J Neural Eng Date: 2018-04 Impact factor: 5.379
Authors: Yukitoshi Izumi; Anil G Cashikar; Kathiresan Krishnan; Steven M Paul; Douglas F Covey; Steven J Mennerick; Charles F Zorumski Journal: J Neurosci Date: 2021-11-01 Impact factor: 6.709
Authors: Charys Palmer; Fabio A Facchini; Richard Po Jones; Frank Neumann; Francesco Peri; Grisha Pirianov Journal: Innate Immun Date: 2021-04 Impact factor: 2.680