Painter Meghan M, Atagi Yuka, Liu Chia-Chen, Rademakers Rosa, Xu Huaxi, Fryer John D, Bu Guojun
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, 361102, China.
Mol Neurodegener. 2015 Sep 4;10:43. doi: 10.1186/s13024-015-0040-9.
Myeloid-lineage cells accomplish a myriad of homeostatic tasks including the recognition of pathogens, regulation of the inflammatory milieu, and mediation of tissue repair and regeneration. The innate immune receptor and its adaptor protein—triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12)—possess the ability to modulate critical cellular functions via crosstalk with diverse signaling pathways. As such, mutations in TREM2 and DAP12 have been found to be associated with a range of disease phenotypes. In particular, mutations in TREM2 increase the risk for Alzheimer's disease and other neurodegenerative disorders. The leading hypothesis is that microglia, the resident immune cells of the central nervous system, are the major myeloid cells affected by dysregulated TREM2-DAP12 function. Here, we review how impaired signaling by the TREM2-DAP12 pathway leads to altered immune responses in phagocytosis, cytokine production, and microglial proliferation and survival, thus contributing to disease pathogenesis.
髓系细胞完成无数的稳态任务，包括病原体识别、炎症微环境调节以及组织修复和再生的介导。固有免疫受体及其衔接蛋白——髓系细胞触发受体2（TREM2）和12 kDa DNAX激活蛋白（DAP12）——具有通过与多种信号通路相互作用来调节关键细胞功能的能力。因此，已发现TREM2和DAP12中的突变与一系列疾病表型相关。特别是，TREM2中的突变会增加患阿尔茨海默病和其他神经退行性疾病的风险。主要假说是，小胶质细胞作为中枢神经系统的常驻免疫细胞，是受TREM2-DAP12功能失调影响的主要髓系细胞。在此，我们综述TREM2-DAP12信号通路受损如何导致吞噬作用、细胞因子产生以及小胶质细胞增殖和存活中的免疫反应改变，从而促进疾病发病机制。
