The TRPM2 ion channel contributes to cytokine hyperproduction in a mouse model of Down Syndrome.
The TRPM2 ion channel contributes to cytokine hyperproduction in a mouse model of Down Syndrome.
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TRPM2 离子通道有助于唐氏综合症小鼠模型中细胞因子的过度产生。
DOI：
10.1016/j.bbadis.2017.09.025
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Perraud,Anne-Laure
中科院分区：
文献类型：
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作者：
Gally,Fabienne;Rao,DeviyaniM;Schmitz,Carsten;Colvin,KelleyL;Yeager,MichaelE;Perraud,Anne-Laure
21三体（唐氏综合征，DS）是最常见的染色体异常。虽然DS主要被认为影响认知能力和心脏健康，但DS患者也表现出免疫功能失调。促炎细胞因子水平增加，但先天免疫的内在改变在DS中研究不足。此外，活性氧（ROS）升高在DS患者中有充分的记录，进一步加剧了炎症过程。慢性炎症和氧化应激通常是随后的组织破坏和病理学的前体，其影响大多数患有DS的人。与ROS一起，第二信使离子Ca 2+在免疫调节中起核心作用。TRPM 2（瞬时受体电位Melastatin 2）是一种在氧化应激条件下激活的Ca 2+渗透性离子通道。Trpm 2基因位于人类21号染色体（Hsa 21）上。TRPM 2在先天免疫细胞中有很强的代表性，许多研究已经证明了它在调节炎症中的作用。我们之前已经发现，由于细胞因子产生不理想，TRPM 2 −/−小鼠对细菌病原体单核细胞增生李斯特菌（Lm）高度敏感。因此，我们使用Lminfection来触发和表征DS小鼠模型Dp 10（yey）中的免疫应答，并研究TRPM 2的潜在贡献。与野生型（WT）相比，Dp 10（yey）小鼠对Lmin感染的抵抗力增强，IFNγ血清浓度升高。使用基因消除的方法，我们表明，这些影响与Trpm 2基因拷贝数，支持的概念，Trpm 2可能会促进炎症过度的DS。
Trisomy 21 (Down Syndrome, DS) is the most common chromosomal anomaly. Although DS is mostly perceived as affecting cognitive abilities and cardiac health, individuals with DS also exhibit dysregulated immune functions. Levels of pro-inflammatory cytokines are increased, but intrinsic alterations of innate immunity are understudied in DS. Furthermore, elevated Reactive Oxygen Species (ROS) are well documented in individuals with DS, further exacerbating inflammatory processes. Chronic inflammation and oxidative stress are often precursors of subsequent tissue destruction and pathologies, which affect a majority of persons with DS.Together with ROS, the second messenger ion Ca2 +plays a central role in immune regulation. TRPM2 (Transient Receptor Potential Melastatin 2) is a Ca2 +-permeable ion channel that is activated under conditions of oxidative stress. The Trpm2 gene is located on human Chromosome 21 (Hsa21). TRPM2 is strongly represented in innate immune cells, and numerous studies have documented its role in modulating inflammation. We have previously found that as a result of suboptimal cytokine production, TRPM2−/−mice are highly susceptible to the bacterial pathogenListeria monocytogenes(Lm). We therefore usedLminfection to trigger and characterize immune responsiveness in the DS mouse model Dp10(yey), and to investigate the potential contribution of TRPM2. In comparison to wildtype (WT), Dp10(yey) mice show an increased resistance againstLminfection and higher IFNγ serum concentrations. Using a gene elimination approach, we show that these effects correlate with Trpm2 gene copy number, supporting the notion that Trpm2 might promote hyperinflammation in DS.