Activating transcription factor 4 underlies the pathogenesis of arsenic trioxide-mediated impairment of macrophage innate immune functions.
Activating transcription factor 4 underlies the pathogenesis of arsenic trioxide-mediated impairment of macrophage innate immune functions.
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激活转录因子 4 是三氧化二砷介导的巨噬细胞先天免疫功能受损的发病机制的基础。
DOI：
10.1016/j.taap.2016.07.015
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发表时间：
2016
影响因子：
3.8
通讯作者：
Athar,Mohammad
中科院分区：
文献类型：
--
作者：
Srivastava,RiteshK;Li,Changzhao;Wang,Yong;Weng,Zhiping;Elmets,CraigA;Harrod,KevinS;Deshane,JessyS;Athar,Mohammad
人类长期接触砷被认为具有免疫抑制作用，对几种传染病的易感性增加。然而，确切的分子机制仍然未知。早些时候，我们发现未折叠蛋白反应（UPR）信号参与砷介导的巨噬细胞功能损伤。在这里，我们表明，激活转录因子4（ATF 4），UPR转录因子，调节三氧化二砷（ATO）介导的巨噬细胞功能失调。在ATO处理的ATF 4 +/+野生型小鼠中，CD 11b表达的显著下调与腹膜和肺巨噬细胞吞噬功能的降低相关。在ATO处理的ATF 4 +/−杂合子小鼠中未观察到这种严重的免疫毒性表型。为了证实这些观察结果，我们在Raw 264.7细胞中证明了ATF 4敲低挽救了ATO介导的巨噬细胞功能损伤，包括细胞因子产生、细菌吞噬和吞噬细菌的清除。ATF 4在巨噬细胞中被ATO持续激活可诱导凋亡，而ATF 4表达的减少可防止ATO诱导的凋亡性细胞死亡。用ATO处理的Raw 264.7细胞也表现出失调的Ca++稳态。ATO诱导Ca++依赖的calpain-1和caspase-12表达，共同调节巨噬细胞凋亡。此外，线粒体调节途径也可诱导细胞凋亡。通过用1，4，5-三磷酸肌醇受体（IP 3R）和电压依赖性阴离子通道（VDAC）抑制剂处理来恢复ATO损伤的ER/线粒体中的Ca++稳态，从而减弱巨噬细胞的先天免疫功能。这些研究确定了ATF 4在砷的巨噬细胞失调和免疫毒性的潜在发病机制中的新作用。
Chronic arsenic exposure to humans is considered immunosuppressive with augmented susceptibility to several infectious diseases. The exact molecular mechanisms, however, remain unknown. Earlier, we showed the involvement of unfolded protein response (UPR) signaling in arsenic-mediated impairment of macrophage functions. Here, we show that activating transcription factor 4 (ATF4), a UPR transcription factor, regulates arsenic trioxide (ATO)-mediated dysregulation of macrophage functions. In ATO-treated ATF4+/+wild-type mice, a significant down-regulation of CD11b expression was associated with the reduced phagocytic functions of peritoneal and lung macrophages. This severe immuno-toxicity phenotype was not observed in ATO-treated ATF4+/−heterozygous mice. To confirm these observations, we demonstrated in Raw 264.7 cells that ATF4 knock-down rescues ATO-mediated impairment of macrophage functions including cytokine production, bacterial engulfment and clearance of engulfed bacteria. Sustained activation of ATF4 by ATO in macrophages induces apoptosis, while diminution of ATF4 expression protects against ATO-induced apoptotic cell death. Raw 264.7 cells treated with ATO also manifest dysregulated Ca++homeostasis. ATO induces Ca++-dependent calpain-1 and caspase-12 expression which together regulated macrophage apoptosis. Additionally, apoptosis was also induced by mitochondria-regulated pathway. Restoring ATO-impaired Ca++homeostasis in ER/mitochondria by treatments with the inhibitors of inositol 1,4,5-trisphosphate receptor (IP3R) and voltage-dependent anion channel (VDAC) attenuate innate immune functions of macrophages. These studies identify a novel role for ATF4 in underlying pathogenesis of macrophage dysregulation and immuno-toxicity of arsenic.