TY - JOUR
T1 - VB-201, an oxidized phospholipid small molecule, inhibits CD14- and Toll-like receptor-2-dependent innate cell activation and constrains atherosclerosis
AU - Mendel, I.
AU - Feige, E.
AU - Yacov, N.
AU - Salem, Y.
AU - Levi, I.
AU - Propheta-Meiran, O.
AU - Shoham, A.
AU - Ishai, E.
AU - George, J.
AU - Harats, D.
AU - Breitbart, E.
PY - 2014/1
Y1 - 2014/1
N2 - 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.
AB - 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.
KW - Atherosclerosis
KW - Monocytes
KW - Oxidized phospholipids
UR - http://www.scopus.com/inward/record.url?scp=84888873120&partnerID=8YFLogxK
U2 - 10.1111/cei.12212
DO - 10.1111/cei.12212
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C2 - 24116867
AN - SCOPUS:84888873120
SN - 0009-9104
VL - 175
SP - 126
EP - 137
JO - Clinical and Experimental Immunology
JF - Clinical and Experimental Immunology
IS - 1
ER -
