Lipopolysaccharide up-regulates the expression of Fcalpha/mu receptor and promotes the binding of oxidized low-density lipoprotein and its IgM antibody complex to activated human macrophages

Natural IgM antibodies against oxidized low-density lipoprotein (oxLDL) can inhibit the binding of oxLDL to macrophages and bacterial infection may deteriorate the pathogenesis of atherosclerosis. However, little is known about the molecular mechanisms underlying the action of bacterial lipopolysaccharide (LPS) in the binding of oxLDL to macrophages, contributing to the formation of foam macrophages. In this study, human monocytes-derived macrophages were cultured and incubated with purified human anti-oxLDL IgM antibodies (HAO-IgM), lipopolysaccharide (LPS) and oxLDL. The HAO-IgM were found specifically inhibited the binding of CuoxLDL to naïve macrophages but failed to inhibit the binding of CuoxLDL to LPS-activated macrophages and promoted the formation of CuoxLDL-mediated foam macrophages. Furthermore, the HAO-IgM F(ab')(2) or pre-incubation with unrelated IgM inhibited the binding of HAO-IgM/CuoxLDL complex to LPS-activated macrophages, suggesting that Fcalpha/mu receptor (Fcamr) may be responsible for the binding of HAO-IgM/CuoxLDL complex to LPS-activated macrophages. Indeed, LPS up-regulated the expression of Fcamr in macrophages in a dose- and time-dependent manner, which was diminished by treatment with anti-TLR4. In addition, LPS induced the phosphorylation of p38MAPK and translocation of NF-kappaB p65, contributing to the up-regulated expression of Fcamr in macrophages as treatment with specific inhibitor for p38MAPK (SB203580) or NF-kappaB (PDTC) attenuated the up-regulation of Fcalpha/mu receptor expression induced by LPS in macrophages. Inhibition of p38MAPK and NF-kappaB decreased the foam cells formation increased by Fcamr expression. These data demonstrated that LPS, through the TLR4 receptor, activated the p38MAPK and NF-kappaB pathways and up-regulate the expression of Fcamr in human macrophages, which promotes the binding of IgM/CuoxLDL complex to macrophages and the formation of foam cells. Therefore, our findings provide a new explanation why bacterial infection deteriorates the pathogenesis of atherosclerosis.