title: Inhibition of monocyte chemotaxis by VB-201, a small molecule lecinoxoid, hinders atherosclerosis development in ApoE⁻/⁻ mice.
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 in vitro 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.
  
  
  CONCLUSIONS
  VB-201, a small-molecule lecinoxoid, exhibited up to 90% inhibition of monocyte chemotaxis in vitro. 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. In vivo, 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.
authors.affiliation: VBL Therapeutics, 6 Jonathan Netanyahu St., Or Yehuda 60376, Israel. Erez@vblrx.com
authors.forename: Erez
authors.initials: E
authors.lastname: Feige
authors.forename: Niva
authors.initials: N
authors.lastname: Yacov
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Salem
authors.forename: Itzhak
authors.initials: I
authors.lastname: Levi
authors.forename: Itzhak
authors.initials: I
authors.lastname: Mendel
authors.forename: Oshrat
authors.initials: O
authors.lastname: Propheta-Meiran
authors.forename: Anat
authors.initials: A
authors.lastname: Shoham
authors.forename: Ravit
authors.initials: R
authors.lastname: Hait-Darshan
authors.forename: Omri
authors.initials: O
authors.lastname: Polonsky
authors.forename: Jacob
authors.initials: J
authors.lastname: George
authors.forename: Dror
authors.initials: D
authors.lastname: Harats
authors.forename: Eyal
authors.initials: E
authors.lastname: Breitbart
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects* / Q000276:immunology; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D005997:Glycerylphosphorylcholine / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D010538:Peritonitis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014280:Triglycerides / Q000097:blood; D014657:Vasculitis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D019707:Receptors, Chemokine; D014280:Triglycerides; D005997:Glycerylphosphorylcholine; D002784:Cholesterol; C552500:1-palmityl-2-(4-carboxybutyl)-sn-glycero-3-phosphocholine
keywords: 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine; 1-palmitoyl-2-glutaryl phosphatidylcholine; Chemotaxis; DC; FACS; G-protein coupled receptor; GPCR; Inflammation; LDL; Lecinoxoids; MCP-1; OxPAPC; OxPL; Oxidized phospholipids; PAPC; PGPC; ROS; dendritic cell; fluorescence-activated cell sorting; low density lipoprotein; monocyte chemotactic protein-1; oxidized PAPC; oxidized phospholipid; reactive oxygen species