Deficiency of α1,6-fucosyltransferase promotes neuroinflammation by increasing the sensitivity of glial cells to inflammatory mediators
Deficiency of α1,6-fucosyltransferase promotes neuroinflammation by increasing the sensitivity of glial cells to inflammatory mediators
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α1,6-岩藻糖基转移酶缺乏通过增加神经胶质细胞对炎症介质的敏感性来促进神经炎症
DOI：
10.1016/j.bbagen.2018.12.008
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发表时间：
2019-03-01
影响因子：
3
通讯作者：
Gu, Jianguo
中科院分区：
文献类型：
--
作者：
Lu, Xu;Zhang, Dongmei;Gu, Jianguo
背景：α 1,6-聚焦转移酶缺陷（Fut8(-/-)）小鼠表现出运动增加和精神分裂症样行为。由于神经炎症是大多数脑部疾病的常见病理改变，因此本研究主要研究Fut8在小胶质细胞和星形胶质细胞中的作用。方法：采用免疫组化染色对脑组织进行分析。采用凝集素blot和western blot分别分析核心聚焦和蛋白表达。通过CRISPR/Cas9系统构建fut8敲除（KO）细胞。结果：与野生型（Fut8(+/+)）和异源型（Fut8(+/-)）小鼠相比，未处理和脂多糖刺激的炎性条件Fut8（-/-）小鼠Iba-1阳性细胞和GFAP阳性细胞数量均显著增加。刺激促炎因子，如ifn - γ和IL-6，诱导初级小胶质细胞和星形胶质细胞以及胶质细胞系中聚焦化的表达水平。与野生型（WT）细胞相比，ifn - γ更容易诱导Fut8-KO BV-2细胞的细胞运动和iNOS表达。类似地，Fut8-KO C6细胞和原代星形胶质细胞用2-fluoro-L- focal（一种特异性聚焦抑制剂）处理后，与ANT细胞相比，对il -6刺激的phospho-STAT3信号传导表现出更高的反应。结论：核心聚焦化通过调节小胶质细胞和星形胶质细胞对炎症介质的敏感性，负向调节神经炎症状态。Fut8（-/-）小鼠的功能紊乱不仅与神经元有关，还与神经胶质细胞功能紊乱有关。一般意义：核心病灶是一种新的中枢神经系统炎症调节因子。
Background: alpha 1,6-Fucosyltransferase-deficient (Fut8(-/-)) mice displayed increased locomotion and schizophrenia-like behaviors. Since neuroinflammation is a common pathological change in most brain diseases, this study was focused on investigating the effects of Fut8 in microglia and astrocytes.Methods: Brain tissues were analyzed using immunohistochemical staining. Core fucosylation and protein expression were analyzed using lectin blot and western blot, respectively. Fut8-knockout (KO) cells were established by the CRISPR/Cas9 system.Results: The number of Iba-1 positive cells and GFAP positive cells were significantly increased in both untreated and lipopolysaccharide stimulated inflammatory conditional Fut8(-/-) mice by comparison with both wild-type (Fut8(+/+)) and hetero (Fut8(+/-)) mice. Stimulation with pro-inflammatory factors, such as IFN-gamma and IL-6, induced expression levels of fucosylation in primary microglia and astrocytes, as well as in glial cell lines. Cell motility and iNOS expression were easily induced by IFN-gamma in Fut8-KO BV-2 cells compared with wild-type (WT) cells. In a similar manner, both Fut8-KO C6 cells and primary astrocytes treated with 2-fluoro-L-fucose, a specific inhibitor for fucosylation, showed a higher response to IL-6-stimulated phospho-STAT3 signaling, compared with ANT cells.Conclusions: Core fucosylation negatively regulates the states of neuroinflammation by modulating the sensitivity of microglia and astrocytes to inflammatory mediators. The disorders of Fut8(-/-) mice are caused not only by neurons but also by glial cell dysfunction.General significance: Core fucose is a novel regulator for neuroinflammation in the central nervous system.