CD14 Is a Key Mediator of Both Lysophosphatidic Acid and Lipopolysaccharide Induction of Foam Cell Formation [Molecular Bases of Disease]

Macrophage uptake of oxidized lowdensity lipoprotein (oxLDL) plays an important role in foam cell formation and the pathogenesis of atherosclerosis. We report here that lysophosphatidic acid (LPA) enhances lipopolysaccharide (LPS)-induced oxLDL uptake in macrophages. Our data revealed that both LPA and LPS highly induce the CD14 expression at messenger RNA and protein levels in macrophages. The role of CD14, one component of the LPS receptor cluster, in LPA-induced biological functions has been unknown. We took several steps to examine the role of CD14 in LPA signaling pathways. Knockdown of CD14 expression nearly completely blocked LPA-, LPSor LPA plus LPS-induced oxLDL uptake in macrophages, demonstrating for the first time that CD14 is a key mediator responsible for both LPAand LPS-induced oxLDL uptake/foam cell formation. To determine the molecular mechanism mediating CD14's function, we demonstrated that both LPA and LPS significantly induce the expression of scavenger receptor A-1 (SR-AI), which has been implicated in lipid-uptake process, and depletion of CD14 levels blocked LPA/LPSinduced SR-AI expression. We further showed that the SR-AI specific antibody, which quenches SR-AI function, blocked LPA and LPS-induced foam cell formation. Thus, SR-AI is the downstream mediator of CD14 in regulating LPA-, LPS-, and LPA/LPS-induced foam cell formation. Taken together, our results provide the first experimental evidence that CD14 is a novel connecting molecule linking both LPA and LPS pathways and is a key mediator responsible for LPA/LPS-induced foam cell formation. The LPA/LPS-CD14-SR-AI nexus might be the new convergent pathway, contributing to the worsening of atherosclerosis.

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