Poliani Pietro Luigi, Wang Yaming, Fontana Elena, Robinette Michelle L, Yamanishi Yoshinori, Gilfillan Susan, Colonna Marco
J Clin Invest. 2015 May;125(5):2161-70. doi: 10.1172/JCI77983. Epub 2015 Apr 20.
Microglia contribute to development, homeostasis, and immunity of the CNS. Like other tissue-resident macrophage populations, microglia express the surface receptor triggering receptor expressed on myeloid cells 2 (TREM2), which binds polyanions, such as dextran sulphate and bacterial LPS, and activates downstream signaling cascades through the adapter DAP12. Individuals homozygous for inactivating mutations in TREM2 exhibit demyelination of subcortical white matter and a lethal early onset dementia known as Nasu-Hakola disease. How TREM2 deficiency mediates demyelination and disease is unknown. Here, we addressed the basis for this genetic association using Trem2(-/-) mice. In WT mice, microglia expanded in the corpus callosum with age, whereas aged Trem2(-/-) mice had fewer microglia with an abnormal morphology. In the cuprizone model of oligodendrocyte degeneration and demyelination, Trem2(-/-) microglia failed to amplify transcripts indicative of activation, phagocytosis, and lipid catabolism in response to myelin damage. As a result, Trem2(-/-) mice exhibited impaired myelin debris clearance, axonal dystrophy, oligodendrocyte reduction, and persistent demyelination after prolonged cuprizone treatment. Moreover, myelin-associated lipids robustly triggered TREM2 signaling in vitro, suggesting that TREM2 may directly sense lipid components exposed during myelin damage. We conclude that TREM2 is required for promoting microglial expansion during aging and microglial response to insults of the white matter.
小胶质细胞对中枢神经系统的发育、稳态和免疫有重要作用。与其他组织驻留巨噬细胞群体一样，小胶质细胞表达髓系细胞触发受体2（TREM2），该受体可结合多聚阴离子，如硫酸葡聚糖和细菌脂多糖，并通过衔接蛋白DAP12激活下游信号级联反应。TREM2基因失活突变的纯合个体表现出皮质下白质脱髓鞘以及一种致命的早发性痴呆，即纳苏-哈科拉病。TREM2缺乏如何介导脱髓鞘和疾病尚不清楚。在此，我们使用Trem2基因敲除小鼠研究了这种基因关联的基础。在野生型小鼠中，胼胝体中的小胶质细胞数量随年龄增长而增加，而老年Trem2基因敲除小鼠的小胶质细胞数量较少且形态异常。在少突胶质细胞变性和脱髓鞘的铜螯合剂模型中，Trem2基因敲除的小胶质细胞在应对髓鞘损伤时未能扩增指示激活、吞噬作用和脂质分解代谢的转录本。因此，Trem2基因敲除小鼠在长期铜螯合剂处理后表现出髓鞘碎片清除受损、轴突营养不良、少突胶质细胞减少和持续脱髓鞘。此外，髓鞘相关脂质在体外强烈触发TREM2信号传导，表明TREM2可能直接感知髓鞘损伤时暴露的脂质成分。我们得出结论，TREM2是衰老过程中促进小胶质细胞扩增以及小胶质细胞对白质损伤作出反应所必需的。
