Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival.
Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival.
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DOI：
10.1016/j.immuni.2013.09.006
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发表时间：
2013-10-17
期刊：
影响因子：
32.4
通讯作者：
Deepe GS Jr
中科院分区：
文献类型：
--
作者：
Subramanian Vignesh K;Landero Figueroa JA;Porollo A;Caruso JA;Deepe GS Jr
巨噬细胞具有许多对抗微生物入侵的机制，包括螯合必需营养素，如锌。多效性细胞因子粒细胞巨噬细胞集落刺激因子（GM-CSF）可增强对胞内病原体（如荚膜组织胞浆菌）的抗菌防御作用，但其作用方式仍不清楚。我们已经发现，GM-CSF激活感染的巨噬细胞螯合不稳定的锌诱导金属硫蛋白（MT）在STAT 3和STAT 5转录因子依赖的方式结合。GM-CSF上调锌出口商，Slc 30 a4和Slc 30 a7的表达和金属穿梭远离吞噬体和进入高尔基体。这种独特的锌螯合策略提高了吞噬体H+通道功能，并引发NADPH氧化酶产生活性氧（ROS）。因此，H. capsulatum选择性地剥夺锌，从而停止复制和促进真菌清除。GM-CSF介导的锌螯合通过MT在体外和体内在小鼠和人巨噬细胞。这些发现阐明了GM-CSF诱导的锌螯合网络，驱动吞噬细胞抗菌效应功能。
Macrophages possess numerous mechanisms to combat microbial invasion, including sequestration of essential nutrients, like Zn. The pleiotropic cytokine granulocyte macrophage-colony stimulating factor (GM-CSF) enhances antimicrobial defenses against intracellular pathogens such as Histoplasma capsulatum, but its mode of action remains elusive. We have found that GM-CSF activated infected macrophages sequestered labile Zn by inducing binding to metallothioneins (MTs) in a STAT3 and STAT5 transcription factor-dependent manner. GM-CSF upregulated expression of Zn exporters, Slc30a4 and Slc30a7 and the metal was shuttled away from phagosomes and into the Golgi apparatus. This distinctive Zn sequestration strategy elevated phagosomal H+ channel function and triggered reactive oxygen species (ROS) generation by NADPH oxidase. Consequently, H. capsulatum was selectively deprived of Zn, thereby halting replication and fostering fungal clearance. GM-CSF mediated Zn sequestration via MTs in vitro and in vivo in mice and in human macrophages. These findings illuminate a GM-CSF-induced Zn-sequestration network that drives phagocyte antimicrobial effector function.
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DOI：
10.1165/ajrcmb.24.3.4238
发表时间：
2001-03-01
影响因子：
6.4
作者：
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影响因子：
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