Differential Modulation of TREM2 Protein during Postnatal Brain Development in Mice

During postnatal development, microglia, the resident innate immune cells of the central nervous system are constantly monitoring the brain parenchyma, cleaning the cell debris, the synaptic contacts overproduced and also maintaining the brain homeostasis. In this context, the postnatal microglia need some control over the innate immune response. One such molecule recently described to be involved in modulation of immune response is TREM2 (triggering receptor expressed on myeloid cells 2). Although some studies have observed TREM2 mRNA in postnatal brain, the regional pattern of the TREM2 protein has not been described. We therefore characterized the distribution of TREM2 protein in mice brain from Postnatal day (P) 1 to 14 by immunostaining. In our study, TREM2 protein was expressed only in microglia/macrophages and is developmentally downregulated in a region-dependent manner. Its expression persisted in white matter, mainly in caudal corpus callosum, and the neurogenic subventricular zone for a longer time than in grey matter. Additionally, the phenotypes of the TREM2+ microglia also differ; expressing CD16/32, MHCII and CD86 (antigen presentation markers) and CD68 (phagocytic marker) in different regions as well as with different intensity till P7. The mannose receptor (CD206) colocalized with TREM2 only at P1–P3 in the subventricular zone and cingulum, while others persisted at low intensities till P7. Furthermore, the spatiotemporal expression pattern and characterization of TREM2 indicate towards its other plausible roles in phagocytosis, progenitor’s fate determination or microglia phenotype modulation during postnatal development. Hence, the increase of TREM2 observed in pathologies may recapitulate their function during postnatal development, as a better understanding of this period may open new pathway for future therapies.产后发育过程中，小胶质细胞（microglia）作为中枢神经系统的固有免疫细胞，持续监测脑实质、清除细胞碎片与过量生成的突触连接，并维持脑内稳态。在此背景下，产后小胶质细胞需要对固有免疫应答进行精准调控。新近被报道参与免疫应答调控的此类分子之一，为髓系细胞触发受体2（triggering receptor expressed on myeloid cells 2，TREM2）。 尽管已有研究在产后大脑中检测到TREM2信使核糖核酸（mRNA），但目前尚未明确TREM2蛋白的区域分布模式。为此，本研究通过免疫染色技术，对产后第1天至第14天（P1至P14）的小鼠大脑中TREM2蛋白的分布特征进行了系统表征。 本研究发现，TREM2蛋白仅表达于小胶质细胞/巨噬细胞中，并呈现区域依赖性的发育性下调模式。其表达在白质中的持续时间长于灰质，主要集中在尾侧胼胝体以及神经发生性室管膜下区。 此外，TREM2阳性小胶质细胞的表型也存在差异：截至产后第7天（P7），其在不同脑区中表达的抗原呈递标志物CD16/32、主要组织相容性复合体II类分子（MHCII）、CD86以及吞噬标志物CD68的强度均有所不同。 仅在产后第1至3天（P1-P3）的室管膜下区与扣带回中，甘露糖受体（CD206）与TREM2存在共定位；其余标志物则持续以低表达水平维持至P7。 进一步的分析显示，TREM2的时空表达模式与特征表明，其在产后发育阶段还可能参与吞噬作用、祖细胞命运决定以及小胶质细胞表型调控等其他生理过程。 因此，病理状态下观察到的TREM2表达上调，可能是其在产后发育阶段功能的重演；对该阶段TREM2功能的深入解析，可为未来的治疗策略提供全新方向。