From Université Lille 2, Lille, France (G.B., S.C., J.V., B.D., C.C., M.F., M.D., L.B., C.Z., B.J., B.S., G.C.-G.); Inserm U1011, Lille, France (G.B., S.C., J.V., B.D., C.C., M.F., M.D., L.B., B.S., G.C.-G.); Institut Pasteur de Lille, France (G.B., S.C., J.V., B.D., C.C., M.F., M.D., L.B., B.S., G.C.-G.); European Genomic Institute for Diabetes, Lille, France (G.B., S.C., J.V., B.D., C.C., M.F., M.D., L.B., B.S., G.C.-G.); and Centre Hospitalier Régional Universitaire de Lille, France (S.H., C.Z., B.J.).
Circ Res. 2013 Nov 8;113(11):1196-205. doi: 10.1161/CIRCRESAHA.113.301656. Epub 2013 Sep 13.
In atherosclerotic plaques, iron preferentially accumulates in macrophages where it can exert pro-oxidant activities.
The objective of this study was, first, to better characterize the iron distribution and metabolism in macrophage subpopulations in human atherosclerotic plaques and, second, to determine whether iron homeostasis is under the control of nuclear receptors, such as the liver X receptors (LXRs).
Here we report that iron depots accumulate in human atherosclerotic plaque areas enriched in CD68 and mannose receptor (MR)-positive (CD68(+)MR(+)) alternative M2 macrophages. In vitro IL-4 polarization of human monocytes into M2 macrophages also resulted in a gene expression profile and phenotype favoring iron accumulation. However, M2 macrophages on iron exposure acquire a phenotype favoring iron release, through a strong increase in ferroportin expression, illustrated by a more avid oxidation of extracellular low-density lipoprotein by iron-loaded M2 macrophages. In line, in human atherosclerotic plaques, CD68(+)MR(+) macrophages accumulate oxidized lipids, which activate LXRα and LXRβ, resulting in the induction of ABCA1, ABCG1, and apolipoprotein E expression. Moreover, in iron-loaded M2 macrophages, LXR activation induces nuclear factor erythroid 2-like 2 expression, thereby increasing ferroportin expression, which, together with a decrease of hepcidin mRNA levels, promotes iron export.
These data identify a role for M2 macrophages in iron handling, a process regulated by LXR activation.
在动脉粥样硬化斑块中，铁优先积聚在巨噬细胞中，从而发挥促氧化作用。
本研究的目的首先是更好地描述人类动脉粥样硬化斑块中巨噬细胞亚群的铁分布和代谢，其次是确定铁稳态是否受核受体（如肝 X 受体 (LXRs)）的控制。
在这里，我们报告铁库在富含 CD68 和甘露糖受体 (MR)阳性 (CD68(+)MR(+)) 替代 M2 巨噬细胞的人动脉粥样硬化斑块区域中积累。体外 IL-4 对人单核细胞向 M2 巨噬细胞的极化也导致了有利于铁积累的基因表达谱和表型。然而，铁暴露的 M2 巨噬细胞通过铁蛋白表达的强烈增加获得了有利于铁释放的表型，这通过铁负载的 M2 巨噬细胞更有效地氧化细胞外低密度脂蛋白得到证明。与此一致，在人类动脉粥样硬化斑块中，CD68(+)MR(+)巨噬细胞积累氧化脂质，激活 LXRα 和 LXRβ，导致 ABCA1、ABCG1 和载脂蛋白 E 的表达诱导。此外，在铁负载的 M2 巨噬细胞中，LXR 激活诱导核因子红细胞 2 样 2 的表达，从而增加铁蛋白的表达，这与铁调素 mRNA 水平的降低一起，促进铁输出。
这些数据确定了 M2 巨噬细胞在铁处理中的作用，这是一个受 LXR 激活调节的过程。
