Inhibition of monocyte chemotaxis by VB-201, a small molecule lecinoxoid, hinders atherosclerosis development in ApoE-/- mice

Erez Feige, Niva Yacov, Yaniv Salem, Itzhak Levi, Itzhak Mendel, Oshrat Propheta-Meiran, Anat Shoham, Ravit Hait-Darshan, Omri Polonsky, Jacob George, Dror Harats, Eyal Breitbart

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Monocytes are motile cells which sense inflammatory stimuli and subsequently migrate to sites of inflammation. Key players in host defense, monocytes have nevertheless been implicated as requisite mediators of several chronic inflammatory diseases. Inhibition of monocyte chemotaxis is therefore an attractive anti-inflammatory strategy. Oxidized phospholipids (OxPL) are native regulators of inflammation, yet their direct effect on monocyte chemotaxis is poorly defined. In this study, we investigated the direct effect of natural and synthetic phospholipids on monocyte chemotaxis. Methods: Exploring various phospholipids using invitro chemotaxis assays, we found that the natural phospholipid 1-palmitoyl-2-glutaryl phosphatidylcholine (PGPC) can decrease monocyte chemotaxis by 50%, while other tested OxPL had no effect. We generated a library of synthetic OxPL designated lecinoxoids, which was screened for anti-inflammatory properties. Results and conclusions: VB-201, a small-molecule lecinoxoid, exhibited up to 90% inhibition of monocyte chemotaxis invitro. Molecular analysis revealed that the effect of VB-201 was not restricted to a specific chemotactic ligand or receptor, and resulted from inhibition of signaling pathways required for monocyte chemotaxis. Interestingly, VB-201 did not inhibit monocyte adhesion or phagocytosis and had no effect on chemotaxis of CD4+ T-cells or neutrophils. Invivo, oral treatment with VB-201 reduced monocyte migration in a peritonitis model and inhibited atheroma development in ApoE-/- mice, without affecting cholesterol or triglyceride levels. Our findings highlight a novel role played by native and synthetic phospholipids in regulation of monocyte chemotaxis. The data strengthen the involvement of phospholipids as key signaling molecules in inflammatory settings and demonstrate their potential therapeutic applicability.

Original languageEnglish
Pages (from-to)430-439
Number of pages10
JournalAtherosclerosis
Volume229
Issue number2
DOIs
StatePublished - Aug 2013
Externally publishedYes

Keywords

  • Chemotaxis
  • Inflammation
  • Lecinoxoids
  • Oxidized phospholipids

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