Glia maturation factor-γ regulates murine macrophage iron metabolism and M2 polarization through mitochondrial ROS
Glia maturation factor-γ regulates murine macrophage iron metabolism and M2 polarization through mitochondrial ROS
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DOI：
10.1182/bloodadvances.2018026070
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发表时间：
2019-04-23
期刊：
影响因子：
7.5
通讯作者：
Rodgers, Griffin P.
中科院分区：
文献类型：
--
作者：
Aerbajinai, Wulin;Ghosh, Manik C.;Rodgers, Griffin P.
在巨噬细胞中，细胞铁代谢状态与巨噬细胞表型紧密结合，并与线粒体功能相关。然而，分子事件如何调节线粒体活性以整合铁代谢和巨噬细胞表型的调节仍不清楚。在此，我们探讨了肌动蛋白调节蛋白胶质成熟因子-γ（GMFG）在调节细胞铁代谢和巨噬细胞表型中的重要作用。我们发现，GMFG下调小鼠巨噬细胞暴露于铁和过氧化氢。GMFG敲低改变了铁代谢蛋白的表达，增加了小鼠巨噬细胞中的铁水平，并伴随着促进其向抗炎M2表型的极化。GMFG敲除巨噬细胞表现出线粒体活性氧（mtROS）水平适度增加，这伴随着一些线粒体呼吸链组分的表达减少，包括铁硫簇组装支架蛋白ISCU以及抗氧化酶SOD 1和SOD 2。重要的是，用抗氧化剂N-乙酰半胱氨酸处理GMFG敲低的巨噬细胞逆转了铁代谢蛋白的表达改变，并显著抑制了M2巨噬细胞标志物的基因表达增强，表明mtROS与细胞铁代谢和巨噬细胞表型机械相关。最后，GMFG与线粒体膜ATP酶ATAD 3A相互作用，表明GMFG敲低诱导的线粒体ROS产生可能归因于巨噬细胞线粒体功能的改变。我们的研究结果表明，GMFG是一个重要的调节细胞铁代谢和巨噬细胞表型，并可能是一个新的治疗目标，调节巨噬细胞功能的免疫和代谢紊乱。
In macrophages, cellular iron metabolism status is tightly integrated with macrophage phenotype and associated with mitochondrial function. However, how molecular events regulate mitochondrial activity to integrate regulation of iron metabolism and macrophage phenotype remains unclear. Here, we explored the important role of the actin-regulatory protein glia maturation factor-gamma (GMFG) in the regulation of cellular iron metabolism and macrophage phenotype. We found that GMFG was downregulated in murine macrophages by exposure to iron and hydrogen peroxide. GMFG knockdown altered the expression of iron metabolism proteins and increased iron levels in murine macrophages and concomitantly promoted their polarization toward an anti-inflammatory M2 phenotype. GMFG-knockdown macrophages exhibited moderately increased levels of mitochondrial reactive oxygen species (mtROS), which were accompanied by decreased expression of some mitochondrial respiration chain components, including the iron-sulfur cluster assembly scaffold protein ISCU as well as the antioxidant enzymes SOD1 and SOD2. Importantly, treatment of GMFG-knockdown macrophages with the antioxidant N-acetylcysteine reversed the altered expression of iron metabolism proteins and significantly inhibited the enhanced gene expression of M2 macrophage markers, suggesting that mtROS is mechanistically linked to cellular iron metabolism and macrophage phenotype. Finally, GMFG interacted with the mitochondrial membrane ATPase ATAD3A, suggesting that GMFG knockdown-induced mtROS production might be attributed to alteration of mitochondrial function in macrophages. Our findings suggest that GMFG is an important regulator in cellular iron metabolism and macrophage phenotype and could be a novel therapeutic target for modulating macrophage function in immune and metabolic disorders.