The synthetic glycolipid-based TLR4 antagonist FP7 negatively regulates <i>in vitro</i> and <i>in vivo</i> haematopoietic and non-haematopoietic vascular TLR4 signalling

Published on 2018-09-12T12:00:00Z (GMT) by
<div><p>TLRs, including TLR4, have been shown to play a crucial role in cardiovascular inflammatory-based diseases. The main goal of this study was to determine the potential of FP7, a synthetic glycolipid active as a TLR4 antagonist, to modulate haematopoietic and non-haematopoietic vascular TLR4 pro-inflammatory signalling. HUVEC, human THP-1 monocytes, THP-1-derived macrophages, mouse RAW-264.7 macrophages and Angiotensin II-infused apolipoprotein E-deficient mice were <i>in vitro</i> and <i>in vivo</i> models, respectively. Western blotting, Ab array and ELISA approaches were used to explore the effect of FP7 on TLR4 functional activity in response to bacterial LPS (<i>in vitro</i>) and endogenous ligands of sterile inflammation (<i>in vitro</i> and <i>in vivo</i>). Following activation of TLR4, <i>in vitro</i> and <i>in vivo</i> data revealed that FP7 inhibited p38 MAPK and p65 NF-kB phosphorylation associated with down-regulation of a number of TLR4-dependent pro-inflammatory proteins. In addition to inhibition of LPS-induced TLR4 signalling, FP7 negatively regulated TLR4 activation in response to ligands of sterile inflammation (hydroperoxide-rich oxidised LDL, <i>in vitro</i> and Angiotensin II infusion, <i>in vivo</i>). These results demonstrate the ability of FP7 to negatively regulate <i>in vitro</i> and <i>in vivo</i> haematopoietic and non-haematopoietic vascular TLR4 signalling both in humans and mice, suggesting the potential therapeutic use of this TLR4 antagonist for pharmacological intervention of vascular inflammatory diseases.</p></div>

Cite this collection

Palmer, Charys; Peri, Francesco; Neumann, Frank; Ahmad, Feroz; Leake, David S.; Pirianov, Grisha (2018): The synthetic glycolipid-based TLR4 antagonist FP7 negatively regulates in vitro and in vivo haematopoietic and non-haematopoietic vascular TLR4 signalling. SAGE Journals. Collection.