Acute maternal oxidant exposure causes susceptibility of the fetal brain to inflammation and oxidative stress.
Acute maternal oxidant exposure causes susceptibility of the fetal brain to inflammation and oxidative stress.
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DOI：
10.1186/s12974-017-0965-8
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发表时间：
2017-09-30
影响因子：
9.3
通讯作者：
Maffi SK
中科院分区：
文献类型：
--
作者：
Akhtar F;Rouse CA;Catano G;Montalvo M;Ullevig SL;Asmis R;Kharbanda K;Maffi SK
母体暴露于环境压力源对胎儿发育构成风险。氧化应激（OS），小胶质细胞激活和炎症是三个紧密联系的机制，出现作为一个因果因素的神经发育异常与产前乙醇暴露。抗氧化剂，如谷胱甘肽（GSH）和CuZnSOD的扰动，他们的操纵提供了证据的神经保护。然而，GSH在子宫内改变对胎儿小胶质细胞活化和炎症的细胞和分子影响仍然难以捉摸。在妊娠第16-17天向妊娠小鼠施用乙醇（EtOH）（2.5 g/kg）。在乙醇处理前1小时，给予N-乙酰半胱氨酸（NAC）和L-丁硫氨酸亚砜亚胺（BSO）以调节胎儿和母体脑中的谷胱甘肽（GSH）含量。乙醇染毒24 h后，测定脑组织中GSH含量和OS。基于细胞因子和趋化因子与独特的小胶质细胞表型M1样（IL-1β、IFN γ、IL-6、CCL 3、CCL 4、CCL-7、CCL 9）或M2样（TGF-β、IL-4、IL-10、CCL 2、CCL 22、CXCL 10、Arg 1、Chi 1、CCR 2和CXCR 2）的相关性选择细胞因子和趋化因子，并通过qRT-PCR和ELISA在脑中进行测量。此外，蛋白质印迹和共聚焦显微镜技术结合EOC13.31细胞暴露于类似的乙醇诱导的氧化应激和氧化还原条件下，用于确定与所观察到的表型变化相关的小胶质细胞活化的潜在机制。我们发现，在妊娠的最后三个月，一次轻度至中度OS的发作导致GSH耗竭，增加蛋白质和脂质过氧化反应和炎症反应倾向于M1样小胶质细胞表型（IL-1β，IFN-γ）在暴露后6-24小时观察到胎儿脑组织。母亲的大脑对许多这些显著的变化有抵抗力。使用EOC 13.31细胞，我们发现小胶质细胞中的GSH稳态对于恢复其抗炎状态和调节炎症至关重要。氧化应激下的小胶质细胞主要维持M1活化状态。此外，GSH耗竭防止M2样表型的出现，同时增强与M1样表型相关的形态学变化。这一观察结果也通过炎性特征（IL-1β、IFN-γ、IL-6、CCL 9、CXCR 2）的表达增加来验证。相反，保存细胞内GSH浓度消除OS，这排除了核转位，更重要的是NFkB p105亚基的磷酸化。这些细胞显示出显著更显著的延长、分支和M2样小胶质细胞表型标志物（IL-10、IL-4、TGF-β、CXCL 10、CCL 22、Chi、Arg和CCR 2）的表达增强。总之，我们的数据表明，保持GSH稳态不仅是重要的淬火OS在发育中的胎儿大脑，但同样重要的是，以提高M2样小胶质细胞表型，从而抑制炎症反应引起的环境应激。本文的在线版本（10.1186/s12974-017-0965-8）包含补充材料，可供授权用户使用。
Maternal exposure to environmental stressors poses a risk to fetal development. Oxidative stress (OS), microglia activation, and inflammation are three tightly linked mechanisms that emerge as a causal factor of neurodevelopmental anomalies associated with prenatal ethanol exposure. Antioxidants such as glutathione (GSH) and CuZnSOD are perturbed, and their manipulation provides evidence for neuroprotection. However, the cellular and molecular effects of GSH alteration in utero on fetal microglia activation and inflammation remain elusive. Ethanol (EtOH) (2.5 g/kg) was administered to pregnant mice at gestational days 16–17. One hour prior to ethanol treatment, N-acetylcysteine (NAC) and L-buthionine sulfoximine (BSO) were administered to modulate glutathione (GSH) content in fetal and maternal brain. Twenty-four hours following ethanol exposure, GSH content and OS in brain tissues were analyzed. Cytokines and chemokines were selected based on their association with distinctive microglia phenotype M1-like (IL-1β, IFN γ, IL-6, CCL3, CCL4, CCL-7, CCL9,) or M2-like (TGF-β, IL-4, IL-10, CCL2, CCL22, CXCL10, Arg1, Chi1, CCR2 and CXCR2) and measured in the brain by qRT-PCR and ELISA. In addition, Western blot and confocal microscopy techniques in conjunction with EOC13.31 cells exposed to similar ethanol-induced oxidative stress and redox conditions were used to determine the underlying mechanism of microglia activation associated with the observed phenotypic changes. We show that a single episode of mild to moderate OS in the last trimester of gestation causes GSH depletion, increased protein and lipid peroxidation and inflammatory responses inclined towards a M1-like microglial phenotype (IL-1β, IFN-γ) in fetal brain tissue observed at 6–24 h post exposure. Maternal brain is resistant to many of these marked changes. Using EOC 13.31 cells, we show that GSH homeostasis in microglia is crucial to restore its anti-inflammatory state and modulate inflammation. Microglia under oxidative stress maintain a predominantly M1 activation state. Additionally, GSH depletion prevents the appearance of the M2-like phenotype, while enhancing morphological changes associated with a M1-like phenotype. This observation is also validated by an increased expression of inflammatory signatures (IL-1β, IFN-γ, IL-6, CCL9, CXCR2). In contrast, conserving intracellular GSH concentrations eliminates OS which precludes the nuclear translocation and more importantly the phosphorylation of the NFkB p105 subunit. These cells show significantly more pronounced elongations, ramifications, and the enhanced expression of M2-like microglial phenotype markers (IL-10, IL-4, TGF-β, CXCL10, CCL22, Chi, Arg, and CCR2). Taken together, our data show that maintaining GSH homeostasis is not only important for quenching OS in the developing fetal brain, but equally critical to enhance M2 like microglia phenotype, thus suppressing inflammatory responses elicited by environmental stressors. The online version of this article (10.1186/s12974-017-0965-8) contains supplementary material, which is available to authorized users.
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影响因子：
3.7
作者：
Imielski Y;Schwamborn JC;Lüningschrör P;Heimann P;Holzberg M;Werner H;Leske O;Püschel AW;Memet S;Heumann R;Israel A;Kaltschmidt C;Kaltschmidt B
通讯作者：
Kaltschmidt B
DOI：
10.1111/j.1530-0277.1995.tb01572.x
发表时间：
1995-06-01
影响因子：
3.2
作者：
HENDERSON, GI;DEVI, BG;SCHENKER, S
通讯作者：
SCHENKER, S
影响因子：
2.9
作者：
Kamencic, H;Lyon, A;Juurlink, BHJ
通讯作者：
Juurlink, BHJ
DOI：
10.2741/henderson
发表时间：
1999-06-15
期刊：
Frontiers in Bioscience
影响因子：
--
作者：
Henderson, George I.;Chen, JuanJuan;Schenker, Steven
通讯作者：
Schenker, Steven
影响因子：
4.5
作者：
Bhang SY;Ha E;Park H;Ha M;Hong YC;Kim BN;Lee SJ;Lee KY;Kim JH;Jeong J;Jeong KS;Lee B;Kim Y
通讯作者：
Kim Y