H San Raffaele Institute, DIBIT-3A1, via Olgettina 58, 20132 Milano, Italy.
Haematologica. 2010 Nov;95(11):1814-22. doi: 10.3324/haematol.2010.023879. Epub 2010 May 29.
Macrophages play a key role in iron homeostasis. In peripheral tissues, they are known to polarize into classically activated (or M1) macrophages and alternatively activated (or M2) macrophages. Little is known on whether the polarization program influences the ability of macrophages to store or recycle iron and the molecular machinery involved in the processes.
Inflammatory/M1 and alternatively activated/M2 macrophages were propagated in vitro from mouse bone-marrow precursors and polarized in the presence of recombinant interferon-γ or interleukin-4. We characterized and compared their ability to handle radioactive iron, the characteristics of the intracellular iron pools and the expression of molecules involved in internalization, storage and export of the metal. Moreover we verified the influence of iron on the relative ability of polarized macrophages to activate antigen-specific T cells.
M1 macrophages have low iron regulatory protein 1 and 2 binding activity, express high levels of ferritin H, low levels of transferrin receptor 1 and internalize--albeit with low efficiency -iron only when its extracellular concentration is high. In contrast, M2 macrophages have high iron regulatory protein binding activity, express low levels of ferritin H and high levels of transferrin receptor 1. M2 macrophages have a larger intracellular labile iron pool, effectively take up and spontaneously release iron at low concentrations and have limited storage ability. Iron export correlates with the expression of ferroportin, which is higher in M2 macrophages. M1 and M2 cells activate antigen-specific, MHC class II-restricted T cells. In the absence of the metal, only M1 macrophages are effective.
Cytokines that drive macrophage polarization ultimately control iron handling, leading to the differentiation of macrophages into a subset which has a relatively sealed intracellular iron content (M1) or into a subset endowed with the ability to recycle the metal (M2).
巨噬细胞在铁稳态中起着关键作用。在周围组织中，它们被认为可极化为经典激活（或 M1）巨噬细胞和选择性激活（或 M2）巨噬细胞。对于极化程序是否影响巨噬细胞储存或回收铁的能力以及涉及这些过程的分子机制，人们知之甚少。
在体外从鼠骨髓前体中增殖炎症性/ M1 和替代性激活/ M2 巨噬细胞，并在重组干扰素-γ或白细胞介素-4的存在下极化。我们对它们处理放射性铁的能力、细胞内铁池的特性以及参与金属内吞、储存和输出的分子的表达进行了特征描述和比较。此外，我们还验证了铁对极化巨噬细胞相对激活抗原特异性 T 细胞能力的影响。
M1 巨噬细胞的铁调节蛋白 1 和 2 结合活性低，表达高水平的铁蛋白 H，低水平的转铁蛋白受体 1，仅在外源铁浓度高时才低效地内化铁。相比之下，M2 巨噬细胞具有高的铁调节蛋白结合活性，表达低水平的铁蛋白 H 和高水平的转铁蛋白受体 1。M2 巨噬细胞具有较大的细胞内可利用铁池，在低浓度下有效摄取并自发释放铁，储存能力有限。铁输出与铁蛋白的表达相关，铁蛋白在 M2 巨噬细胞中表达更高。M1 和 M2 细胞激活抗原特异性、MHC Ⅱ类限制的 T 细胞。在没有金属的情况下，只有 M1 巨噬细胞有效。
驱动巨噬细胞极化的细胞因子最终控制铁的处理，导致巨噬细胞分化为具有相对封闭的细胞内铁含量的亚群（M1）或具有回收金属能力的亚群（M2）。
