VB-201, an oxidized phospholipid small molecule, inhibits CD14- and Toll-like receptor-2-dependent innate cell activation and constrains atherosclerosis.

Abstract

Atherosclerosis is an inflammatory disease of the vascular wall. Activated monocytes and dendritic cells (DC) in the intima layer of the vasculature promote atherogenesis. Toll-like receptor (TLR)-2 and TLR-4, which are predominantly expressed on these cells and mediate their activation, are essential for atherosclerosis development. In this study we demonstrate that VB-201, an oxidized phospholipid (Ox-PL) small molecule, inhibits TLR signalling restricted to TLR-2 and TLR-4 in human and mouse monocytes and DC. Mechanistically, we show that VB-201 binds directly to TLR-2 and CD14, the TLR-4 co-receptor, to impair downstream cues and cytokine production. In a rabbit model, oral administration of VB-201 constrained atherosclerosis progression. This effect was not due to reduced cholesterol abundance, as hyperlipidaemia was sustained. We suggest that VB-201 may counter inflammation where TLR-2 and/or CD14 complicity is essential, and is therefore beneficial for the treatment of atherosclerosis.

• Authors: I Mendel, E Feige, N Yacov, Y Salem, I Levi, O Propheta-Meiran, A Shoham, E Ishai, J George, D Harats, E Breitbart
• Journal: Clinical and experimental immunology (Clin Exp Immunol) Vol. 175 Issue 1 Pg. 126-37 (Jan 2014) ISSN: 1365-2249 [Electronic] England
• PMID: 24116867 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 British Society for Immunology.

Chemical References

• Lipopolysaccharide Receptors
• TLR2 protein, human
• TLR4 protein, human
• Tlr2 protein, mouse
• Tlr4 protein, mouse
• Toll-Like Receptor 2
• Toll-Like Receptor 4
• Glycerylphosphorylcholine
• Cholesterol
• 1-palmityl-2-(4-carboxybutyl)-sn-glycero-3-phosphocholine

Topics

• Animals
• Atherosclerosis (drug therapy, genetics, immunology, metabolism, pathology)
• Cholesterol (genetics, immunology, metabolism)
• Glycerylphosphorylcholine (pharmacology)
• HEK293 Cells
• Humans
• Immunity, Innate (drug effects, genetics)
• Lipopolysaccharide Receptors (genetics, immunology, metabolism)
• Male
• Mice
• Monocytes (immunology, metabolism)
• Rabbits
• Signal Transduction (drug effects, genetics, immunology)
• Toll-Like Receptor 2 (genetics, immunology, metabolism)
• Toll-Like Receptor 4 (genetics, immunology, metabolism)