The CCR2-mediated recruitment of monocytes into the vessel wall plays an im
portant role in all stages of atherosclerosis. In recent studies, we have s
hown that lipoproteins can modulate CCR2 expression and have identified nat
ive LDL as a positive regulator. In contrast, oxidized LDL (OxLDL), which i
s mainly formed in the aortic intima, reduces CCR2 expression, promotes mon
ocyte retention, and may cause pathological accumulation of monocytes in th
e vessel wall. We now provide evidence that OxLDL reduces monocyte CCR2 exp
ression by activating intracellular signaling pathways that may involve per
oxisome proliferator-activated receptor gamma (PPAR gamma). Receptor-mediat
ed uptake of the lipoprotein particle was required and allows for delivery
of the exogenous ligand to the nuclear receptor. The suppression of CCR2 ex
pression by OxLDL was mediated by lipid components of OxLDL, such as the ox
idized linoleic acid metabolites 9-HODE and 13-HODE, known activators of PP
AR gamma. Modified apoB had no such effect. Consistent with a participation
of the PPAR gamma signaling pathway, BRL49653 reduced CCR2 expression in f
reshly isolated human monocytes ex vivo and in circulating mouse monocytes
in vivo. These results implicate PPAR gamma in the inhibition of CCR2 gene
expression by oxidized lipids, which may help retain monocytes at sites of
inflammation, such as the atherosclerotic lesion.