A novel small molecule TLR4 antagonist (IAXO-102) negatively regulates non-hematopoietic toll like receptor 4 signalling and inhibits aortic aneurysms development.

Atherosclerosis
Christopher HugginsGrisha Pirianov

Abstract

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. 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. 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. These results demonstrate the ability of IA...Continue Reading

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Citations

Apr 14, 2016·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Beatriz SalvadorManuel Fresno
Jun 7, 2018·Physiological Reviews·Steven J ForresterSatoru Eguchi
Nov 16, 2019·Journal of Cardiovascular Pharmacology·Qi-Yang YinYun-Man Li
Mar 6, 2021·Indian Journal of Gastroenterology : Official Journal of the Indian Society of Gastroenterology·Janine S Y TamJoanne M Bowen
Aug 29, 2021·Pharmacology & Therapeutics·Pilar Garcia-VelloAntonio Molinaro

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