Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Changle West Road No. 17, Xi'an 710032, PR China.
Atherosclerosis. 2010 Feb;208(2):396-405. doi: 10.1016/j.atherosclerosis.2009.07.035. Epub 2009 Jul 23.
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.
天然 IgM 抗体可抑制氧化型低密度脂蛋白（oxLDL）与巨噬细胞的结合，细菌感染可能会加重动脉粥样硬化的发病机制。然而，关于细菌脂多糖（LPS）在 oxLDL 与巨噬细胞结合中作用的分子机制知之甚少，这有助于泡沫巨噬细胞的形成。在这项研究中，培养并孵育人单核细胞衍生的巨噬细胞，并用纯化的人抗 oxLDL IgM 抗体（HAO-IgM）、脂多糖（LPS）和 oxLDL 处理。发现 HAO-IgM 可特异性抑制 CuoxLDL 与幼稚巨噬细胞的结合，但不能抑制 LPS 激活的巨噬细胞与 CuoxLDL 的结合，并促进 CuoxLDL 介导的泡沫巨噬细胞的形成。此外，HAO-IgM F(ab')(2) 或与无关 IgM 预孵育可抑制 HAO-IgM/CuoxLDL 复合物与 LPS 激活的巨噬细胞的结合，表明 Fcalpha/mu 受体（Fcamr）可能负责 HAO-IgM/CuoxLDL 复合物与 LPS 激活的巨噬细胞的结合。事实上，LPS 以剂量和时间依赖的方式上调巨噬细胞中 Fcamr 的表达，而 TLR4 的拮抗作用则降低了 Fcamr 的表达。此外，LPS 诱导 p38MAPK 的磷酸化和 NF-kappaB p65 的易位，导致巨噬细胞中 Fcamr 的表达上调，而特异性 p38MAPK（SB203580）或 NF-kappaB（PDTC）抑制剂的处理则减弱了 LPS 诱导的巨噬细胞中 Fcalpha/mu 受体表达的上调。抑制 p38MAPK 和 NF-kappaB 可减少由 Fcamr 表达增加引起的泡沫细胞形成。这些数据表明，LPS 通过 TLR4 受体激活 p38MAPK 和 NF-kappaB 途径，上调人巨噬细胞中 Fcamr 的表达，促进 IgM/CuoxLDL 复合物与巨噬细胞的结合和泡沫细胞的形成。因此，我们的发现提供了一个新的解释，即细菌感染如何加重动脉粥样硬化的发病机制。
