Hasselt University/Transnational University Limburg, Biomedical Research Institute, School of Life Sciences, Diepenbeek, Belgium.
PLoS One. 2012;7(9):e44998. doi: 10.1371/journal.pone.0044998. Epub 2012 Sep 12.
Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the central nervous system in which macrophages and microglia play a central role. Foamy macrophages and microglia, containing degenerated myelin, are abundantly found in active multiple sclerosis lesions. Recent studies have described an altered macrophage phenotype after myelin internalization. However, it is unclear by which mechanisms myelin affects the phenotype of macrophages and how this phenotype can influence lesion progression. Here we demonstrate, by using genome wide gene expression analysis, that myelin-phagocytosing macrophages have an enhanced expression of genes involved in migration, phagocytosis and inflammation. Interestingly, myelin internalization also induced the expression of genes involved in liver-X-receptor signaling and cholesterol efflux. In vitro validation shows that myelin-phagocytosing macrophages indeed have an increased capacity to dispose intracellular cholesterol. In addition, myelin suppresses the secretion of the pro-inflammatory mediator IL-6 by macrophages, which was mediated by activation of liver-X-receptor β. Our data show that myelin modulates the phenotype of macrophages by nuclear receptor activation, which may subsequently affect lesion progression in demyelinating diseases such as multiple sclerosis.
多发性硬化症是一种中枢神经系统的慢性、炎症性、脱髓鞘疾病，其中巨噬细胞和小胶质细胞起着核心作用。泡沫状巨噬细胞和含退化髓磷脂的小胶质细胞在活跃的多发性硬化症病变中大量存在。最近的研究描述了髓磷脂内化后巨噬细胞表型的改变。然而，髓磷脂如何影响巨噬细胞的表型以及这种表型如何影响病变进展尚不清楚。在这里，我们通过全基因组基因表达分析表明，吞噬髓磷脂的巨噬细胞中参与迁移、吞噬和炎症的基因表达增强。有趣的是，髓磷脂内化也诱导了肝 X 受体信号和胆固醇流出相关基因的表达。体外验证表明，吞噬髓磷脂的巨噬细胞确实具有增强的处理细胞内胆固醇的能力。此外，髓磷脂通过激活肝 X 受体 β 抑制巨噬细胞促炎介质 IL-6 的分泌。我们的数据表明，髓磷脂通过核受体激活来调节巨噬细胞的表型，这可能随后影响脱髓鞘疾病（如多发性硬化症）中的病变进展。
