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

Clin Exp Immunol. 2014 Jan;175(1):126-37. doi: 10.1111/cei.12212.

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.

Keywords: atherosclerosis; monocytes; oxidized phospholipids.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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