Age-dependent changes on TGFβ1 Smad3 pathway modify the pattern of microglial cell activation.
Age-dependent changes on TGFβ1 Smad3 pathway modify the pattern of microglial cell activation.
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DOI：
10.1016/j.bbi.2013.12.018
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发表时间：
2014-03
影响因子：
15.1
通讯作者：
von Bernhardi, Rommy
中科院分区：
文献类型：
--
作者：
Tichauer, Juan E.;Flores, Betsi;Soler, Bernardita;Eugenin-von Bernhardi, Laura;Ramirez, Gigliola;von Bernhardi, Rommy
关键词：
衰老是阿尔茨海默病的主要危险因素。在其他特征中，它显示炎症信号的变化可能影响神经胶质细胞活化的调节。我们已经证明星形胶质细胞通过tgf - β1介导的机制预防小胶质细胞的细胞毒性。然而，尽管tgf - β1增加，胶质细胞的激活在衰老过程中持续存在。为了理解这种明显的矛盾，我们研究了衰老过程中tgf - β1- smad3信号传导及其对小胶质细胞功能的影响。在成年小鼠中，tgf - β1通过炎症刺激诱导和激活海马中Smad3信号的作用大大降低。我们评估了tgf - β1- smad3通路对不同年龄小鼠一氧化氮（NO）和活性氧（ROS）分泌以及小胶质细胞吞噬的调节作用，并在体内用脂多糖（LPS）诱导炎症状态。暴露于LPS的年轻小鼠的小胶质细胞只诱导NO分泌，并通过炎症预处理增强，而在成年小鼠中，ROS的诱导占主导地位。tgf - β1分别调节年轻和成年小胶质细胞NO和ROS生成的诱导。调节部分依赖于Smad3途径，并被炎症预处理破坏。炎症和tgf - β1仅在幼鼠小胶质细胞培养物中诱导吞噬。Smad3抑制也阻止了tgf - β1的诱导。我们的研究结果表明，tgf - β1- smad3通路的激活在衰老过程中受损。tgf - β1- smad3的年龄相关损伤可以降低保护性激活，同时促进小胶质细胞的细胞毒性激活，增强小胶质细胞介导的神经变性。
Aging is the main risk factor for Alzheimer's disease. Among other characteristics, it shows changes in inflammatory signaling that could affect the regulation of glial cell activation. We have shown that astrocytes prevent microglial cell cytotoxicity by mechanisms mediated by TGFβ1. However, whereas TGFβ1 is increased, glial cell activation persists in aging. To understand this apparent contradiction, we studied TGFβ1-Smad3 signaling during aging and their effect on microglial cell function. TGFβ1 induction and activation of Smad3 signaling in the hippocampus by inflammatory stimulation was greatly reduced in adult mice. We evaluated the effect of TGFβ1-Smad3 pathway on the regulation of nitric oxide (NO) and reactive oxygen species (ROS) secretion, and phagocytosis of microglia from mice at different ages with and without in vivo treatment with lipopolysaccharide (LPS) to induce an inflammatory status. NO secretion was only induced on microglia from young mice exposed to LPS, and was potentiated by inflammatory preconditioning, whereas in adult mice the induction of ROS was predominant. TGFβ1 modulated induction of NO and ROS production in young and adult microglia, respectively. Modulation was partially dependent on Smad3 pathway and was impaired by inflammatory preconditioning. Phagocytosis was induced by inflammation and TGFβ1 only in microglia cultures from young mice. Induction by TGFβ1 was also prevented by Smad3 inhibition. Our findings suggest that activation of the TGFβ1-Smad3 pathway is impaired in aging. Age-related impairment of TGFβ1-Smad3 can reduce protective activation while facilitating cytotoxic activation of microglia, potentiating microglia-mediated neurodegeneration.
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影响因子：
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通讯作者：
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影响因子：
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