Macrophage uptake and accumulation of folates are polarization‐dependent in vitro and in vivo and are regulated by activin A
Macrophage uptake and accumulation of folates are polarization‐dependent in vitro and in vivo and are regulated by activin A
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DOI：
10.1189/jlb.0613345
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发表时间：
2014-05
影响因子：
5.5
通讯作者：
R. Samaniego;Blanca Soler Palacios;Ángeles Domiguez-Soto;C. Vidal;A. Salas;T. Matsuyama;C. Sánchez-Torres;Inmaculada Torre;M. Miranda-Carús;P. Sánchez-Mateos;A. Puig‐Kröger
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文献类型：
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作者：
R. Samaniego;Blanca Soler Palacios;Ángeles Domiguez-Soto;C. Vidal;A. Salas;T. Matsuyama;C. Sánchez-Torres;Inmaculada Torre;M. Miranda-Carús;P. Sánchez-Mateos;A. Puig‐Kröger
维生素B 9，通常称为叶酸，是一种重要的辅助因子，通过三种主要的专门转运分子（RFC，FR和PCFT）进入细胞，它们在表达模式，底物亲和力和配体结合pH依赖性方面有所不同。我们现在报告，叶酸转运蛋白的表达在巨噬细胞亚型之间存在差异，并解释了体外和体内M2巨噬细胞中5-MTHF（血清中发现的主要叶酸形式）的较高蓄积。M1巨噬细胞表现出较高的RFC表达，而FRβ和PCFT优先由抗炎和稳态M2巨噬细胞表达。在参与叶酸转运的正常组织（胎盘、肝脏、结肠）和炎症组织（溃疡性结肠炎，RA）的巨噬细胞中也观察到这些差异，因为正常组织的M2样巨噬细胞表达FRβ和PCFT，而炎症组织的表达TNF-α的M1巨噬细胞为RFC+。此外，我们提供的证据表明，激活素A是控制巨噬细胞中叶酸转运蛋白集的关键因素，因为它下调FRβ，上调RFC表达，并调节5-MTHF摄取。所有这些实验都支持叶酸处理依赖于巨噬细胞极化阶段的观点。
Vitamin B9, commonly known as folate, is an essential cofactor for one‐carbon metabolism that enters cells through three major specialized transporter molecules (RFC, FR, and PCFT), which differ in expression pattern, affinity for substrate, and ligand‐binding pH dependency. We now report that the expression of the folate transporters differs between macrophage subtypes and explains the higher accumulation of 5‐MTHF—the major folate form found in serum—in M2 macrophages in vitro and in vivo. M1 macrophages display a higher expression of RFC, whereas FRβ and PCFT are preferentially expressed by anti‐inflammatory and homeostatic M2 macrophages. These differences are also seen in macrophages from normal tissues involved in folate transit (placenta, liver, colon) and inflamed tissues (ulcerative colitis, RA), as M2‐like macrophages from normal tissues express FRβ and PCFT, whereas TNF‐α‐expressing M1 macrophages from inflamed tissues are RFC+. Besides, we provide evidences that activin A is a critical factor controlling the set of folate transporters in macrophages, as it down‐regulates FRβ, up‐regulates RFC expression, and modulates 5‐MTHF uptake. All of these experiments support the notion that folate handling is dependent on the stage of macrophage polarization.