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首页> 外文期刊>Immunology: An Official Journal of the British Society for Immunology >Differential regulation of acid sphingomyelinase in macrophages stimulated with oxidized low-density lipoprotein (LDL) and oxidized LDL immune complexes: Role in phagocytosis and cytokine release
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Differential regulation of acid sphingomyelinase in macrophages stimulated with oxidized low-density lipoprotein (LDL) and oxidized LDL immune complexes: Role in phagocytosis and cytokine release

机译：氧化型低密度脂蛋白（LDL）和氧化型LDL免疫复合物刺激的巨噬细胞中酸性鞘磷脂酶的差异调节：在吞噬作用和细胞因子释放中的作用

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Oxidized low-density lipoprotein (oxLDL) and oxLDL-containing immune complexes (oxLDL-IC) contribute to the formation of lipid-laden macrophages (foam cells). Fcγ receptors mediate uptake of oxLDL-IC, whereas scavenger receptors internalize oxLDL. We have previously reported that oxLDL-IC, but not free oxLDL, activate macrophages and prolong their survival. Sphingomyelin is a major constituent of cell membranes and lipoprotein particles and acid sphingomyelinase (ASMase) hydrolyses sphingomyelin to generate the bioactive lipid ceramide. ASMase exists in two forms: lysosomal (L-ASMase) and secretory (S-ASMase). In this study we examined whether oxLDL and oxLDL-IC regulate ASMase differently, and whether ASMase mediates monocyte/macrophage activation and cytokine release. The oxLDL-IC, but not oxLDL, induced early and consistent release of catalytically active S-ASMase. The oxLDL-IC also consistently stimulated L-ASMase activity, whereas oxLDL induced a rapid transient increase in L-ASMase activity before it steadily declined below baseline. Prolonged exposure to oxLDL increased L-ASMase activity; however, activity remained significantly lower than that induced by oxLDL-IC. Further studies were aimed at defining the function of the activated ASMase. In response to oxLDL-IC, heat-shock protein 70B' (HSP70B') was up-regulated and localized with redistributed ASMase in the endosomal compartment outside the lysosome. Treatment with oxLDL-IC induced the formation and release of HSP70-containing and IL-1β-containing exosomes via an ASMase-dependent mechanism. Taken together, the results suggest that oxLDL and oxLDL-IC differentially regulate ASMase activity, and the pro-inflammatory responses to oxLDL-IC are mediated by prolonged activation of ASMase. These findings may contribute to increased understanding of mechanisms mediating macrophage involvement in atherosclerosis.
机译：氧化的低密度脂蛋白（oxLDL）和含oxLDL的免疫复合物（oxLDL-IC）有助于形成负载脂质的巨噬细胞（泡沫细胞）。 Fcγ受体介导oxLDL-IC的摄取，而清道夫受体将oxLDL内在化。我们以前曾报道过oxLDL-IC，但不是游离的oxLDL，可以激活巨噬细胞并延长其生存期。鞘磷脂是细胞膜和脂蛋白颗粒的主要成分，酸性鞘磷脂酶（ASMase）水解鞘磷脂以产生生物活性脂质神经酰胺。 ASMase以两种形式存在：溶酶体（L-ASMase）和分泌性（S-ASMase）。在这项研究中，我们检查了oxLDL和oxLDL-IC是否对ASMase的调节不同，以及ASMase是否介导单核细胞/巨噬细胞激活和细胞因子释放。 oxLDL-IC（而不是oxLDL）诱导了催化活性S-ASMase的早期持续释放。 oxLDL-IC还持续刺激L-ASMase活性，而oxLDL则在L-ASMase活性稳定下降至基线以下之前诱导L-ASMase活性快速瞬时增加。长时间暴露于oxLDL会增加L-ASMase活性;但是，活性仍然明显低于oxLDL-IC诱导的活性。进一步的研究旨在确定激活的ASMase的功能。响应oxLDL-IC，热休克蛋白70B'（HSP70B'）被上调并在溶酶体外部的内体区室中以重新分布的ASMase定位。 oxLDL-IC处理通过ASMase依赖性机制诱导了含HSP70和含IL-1β的外泌体的形成和释放。两者合计，结果表明oxLDL和oxLDL-IC差异调节ASMase活性，并且对oxLDL-IC的促炎反应是由ASMase的长期激活介导的。这些发现可能有助于增进对介导巨噬细胞参与动脉粥样硬化的机制的了解。

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