Opposing roles of the triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells-like transcript 2 in microglia activation.
Opposing roles of the triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells-like transcript 2 in microglia activation.
复制标题
髓样细胞 2 上表达的触发受体和髓样细胞样转录物 2 上表达的触发受体在小胶质细胞激活中的相反作用
DOI：
10.1016/j.neurobiolaging.2016.03.004
复制
发表时间：
2016-06
影响因子：
4.2
通讯作者：
Bu G
中科院分区：
文献类型：
--
作者：
Zheng H;Liu CC;Atagi Y;Chen XF;Jia L;Yang L;He W;Zhang X;Kang SS;Rosenberry TL;Fryer JD;Zhang YW;Xu H;Bu G
TREM 2中的突变已被提出来调节炎症反应和凋亡神经元和/或淀粉样蛋白-β（Aβ）的清除，其在遗传上与迟发性阿尔茨海默病（AD）的风险增加相关。有趣的是，TREM样转录本2（TREML 2）中的一种错义变体（TREML 2）是一种结构相似的蛋白质，由6号染色体上与TREM 2相同的基因簇编码，已被证明可以预防AD。然而，TREM 2和TREML 2调节AD发病机制的分子机制以及它们的功能关系（如果有的话）仍然不清楚。在这里，我们表明脂多糖（LPS）刺激显着抑制TREM 2，但增加小鼠脑中的TREML 2表达。与该体内结果一致，LPS或寡聚Aβ处理下调了原代小胶质细胞中的TREM 2，但上调了TREML 2表达。重要的是，TREM 2或TREML 2水平的调节对炎症反应具有相反的作用，在TREM 2或TREML 2下调时分别观察到LPS诱导的促炎细胞因子基因表达的增强或抑制。此外，当TREM 2下调时，原代小胶质细胞的增殖显著降低，而当TREML 2敲低时，增殖增加。总之，我们的研究结果表明，一些小胶质细胞的功能受到TREM 2和TREML 2的严格调节，其功能障碍可能通过损害大脑先天免疫而导致AD发病。我们的研究结果为小胶质细胞中TREM 2和TREML 2的功能提供了新的机制见解，并对设计治疗AD的新治疗策略具有影响。
Mutations in TREM2, which has been proposed to regulate the inflammatory responses and the clearance of apoptotic neurons and/or amyloid-β (Aβ), are genetically linked to increased risk for late-onset Alzheimer’s disease (AD). Interestingly, a missense variant in TREM-like transcript 2 (TREML2), a structurally similar protein encoded by the same gene cluster with TREM2 on chromosome 6, has been shown to protect against AD. However, the molecular mechanisms by which TREM2 and TREML2 regulate the pathogenesis of AD, and their functional relationship, if any, remain unclear. Here, we show that lipopolysaccharide (LPS) stimulation significantly suppressed TREM2 but increased TREML2 expression in mouse brain. Consistent with this in vivo result, LPS or oligomeric Aβ treatment down-regulated TREM2 but up-regulated TREML2 expression in primary microglia. Importantly, modulation of TREM2 or TREML2 levels had opposing effects on inflammatory responses with enhancement or suppression of LPS induced pro-inflammatory cytokine gene expression observed upon TREM2 or TREML2 down-regulation, respectively. In addition, the proliferation of primary microglia was significantly decreased when TREM2 was down-regulated, whereas it was increased upon TREML2 knockdown. Together, our results suggest that several microglial functions are strictly regulated by TREM2 and TREML2, whose dysfunctions likely contribute to AD pathogenesis by impairing brain innate immunity. Our findings provide novel mechanistic insights into the functions of TREM2 and TREML2 in microglia and have implications on designing new therapeutic strategies to treat AD.