title: 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.affiliation: VBL Therapeutics, Or Yehuda, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Mendel
authors.forename: E
authors.initials: E
authors.lastname: Feige
authors.forename: N
authors.initials: N
authors.lastname: Yacov
authors.forename: Y
authors.initials: Y
authors.lastname: Salem
authors.forename: I
authors.initials: I
authors.lastname: Levi
authors.forename: O
authors.initials: O
authors.lastname: Propheta-Meiran
authors.forename: A
authors.initials: A
authors.lastname: Shoham
authors.forename: E
authors.initials: E
authors.lastname: Ishai
authors.forename: J
authors.initials: J
authors.lastname: George
authors.forename: D
authors.initials: D
authors.lastname: Harats
authors.forename: E
authors.initials: E
authors.lastname: Breitbart
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005997:Glycerylphosphorylcholine / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects* / Q000235:genetics; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D018950:Lipopolysaccharide Receptors; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D005997:Glycerylphosphorylcholine; D002784:Cholesterol; C552500:1-palmityl-2-(4-carboxybutyl)-sn-glycero-3-phosphocholine
keywords: atherosclerosis; monocytes; oxidized phospholipids