Genome-wide association studies have reported that, amongst other microglial genes, variants in TREM2 can profoundly increase the incidence of developing Alzheimer’s disease (ad). We have investigated the role of TREM2 in primary microglial cultures from wild type mice by using siRNA to decrease Trem2 expression, and in parallel from knock-in mice heterozygous or homozygous for the Trem2 R47H ad risk variant. The prevailing phenotype of Trem2 R47H knock-in mice was decreased expression levels of Trem2 in microglia, which resulted in decreased density of microglia in the hippocampus. Overall, primary microglia with reduced Trem2 expression, either by siRNA or from the R47H knock-in mice, displayed a similar phenotype. Comparison of the effects of decreased Trem2 expression under conditions of LPS pro-inflammatory or IL-4 anti-inflammatory stimulation revealed the importance of Trem2 in driving a number of the genes up-regulated in the anti-inflammatory phenotype. RNA-seq analysis showed that IL-4 induced the expression of a programme of genes including Arg1 and Ap1b1 in microglia, which showed an attenuated response to IL-4 when Trem2 expression was decreased. Genes showing a similar expression profile to Arg1 were enriched for STAT6 transcription factor recognition elements in their promoter, and Trem2 knockdown decreased levels of STAT6. LPS-induced pro-inflammatory stimulation suppressed Trem2 expression, thus preventing TREM2’s anti-inflammatory drive. Given that anti-inflammatory signaling is associated with tissue repair, understanding the signaling mechanisms downstream of Trem2 in coordinating the pro- and anti-inflammatory balance of microglia, particularly mediating effects of the IL-4-regulated anti-inflammatory pathway, has important implications for fighting neurodegenerative disease.

中文翻译：

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Trem2 促进小胶质细胞的抗炎反应，并在促炎条件下被抑制。

全基因组关联研究报告称，在其他小胶质细胞基因中，TREM2 中的变异可显着增加阿尔茨海默病的发病率 ( ad )。我们已经通过使用 siRNA 降低Trem2表达，以及平行于Trem2 R47H ad风险变体的杂合或纯合敲入小鼠，研究了 TREM2 在来自野生型小鼠的原代小胶质细胞培养物中的作用。Trem2 R47H 敲入小鼠的主要表型是小胶质细胞中Trem2 的表达水平降低，这导致海马中小胶质细胞的密度降低。总体而言，Trem2减少的初级小胶质细胞通过 siRNA 或来自 R47H 敲入小鼠的表达表现出相似的表型。比较LPS 促炎或 IL-4 抗炎刺激条件下Trem2表达降低的影响，揭示了Trem2在驱动抗炎表型中上调的许多基因中的重要性。RNA-seq 分析表明，IL-4 诱导了小胶质细胞中包括Arg1和Ap1b1在内的基因程序的表达，当Trem2表达降低时，小胶质细胞对 IL-4 的反应减弱。显示与Arg1相似表达谱的基因在其启动子中富含 STAT6 转录因子识别元件，并且Trem2敲低降低了 STAT6 的水平。LPS 诱导的促炎刺激抑制了Trem2 的表达，从而阻止了 TREM2 的抗炎驱动。鉴于抗炎信号与组织修复相关，了解Trem2下游在协调小胶质细胞促炎和抗炎平衡方面的信号机制，尤其是介导 IL-4 调节的抗炎通路的作用，具有重要意义用于对抗神经退行性疾病。