Kober Daniel L, Brett Tom J
Molecular Microbiology and Microbial Pathogenesis Program, Washington University School of Medicine, St. Louis, MO 63110, USA; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
J Mol Biol. 2017 Jun 2;429(11):1607-1629. doi: 10.1016/j.jmb.2017.04.004. Epub 2017 Apr 19.
The protein triggering receptor expressed on myeloid cells-2 (TREM2) is an immunomodulatory receptor with a central role in myeloid cell activation and survival. In recent years, the importance of TREM2 has been highlighted by the identification of coding variants that increase risk for Alzheimer's disease and other neurodegenerative diseases. Animal studies have further shown the importance of TREM2 in neurodegenerative and other inflammatory disease models including chronic obstructive pulmonary disease, multiple sclerosis, and stroke. A mechanistic understanding of TREM2 function remains elusive, however, due in part to the absence of conclusive information regarding the identity of endogenous TREM2 ligands. While many TREM2 ligands have been proposed, their physiological role and mechanism of engagement remain to be determined. In this review, we highlight the suggested roles of TREM2 in these diseases and the recent advances in our understanding of TREM2 and discuss putative TREM2-ligand interactions and their potential roles in signaling during health and disease. We develop a model based on the TREM2 structure to explain how different TREM2 ligands might interact with the receptor and how disease risk variants may alter ligand interactions. Finally, we propose future experimental directions to establish the role and importance of these different interactions on TREM2 function.
髓系细胞触发受体2（TREM2）是一种免疫调节受体，在髓系细胞的激活和存活中起核心作用。近年来，编码变体的鉴定突出了TREM2的重要性，这些变体增加了患阿尔茨海默病和其他神经退行性疾病的风险。动物研究进一步表明TREM2在神经退行性疾病和其他炎症性疾病模型中的重要性，包括慢性阻塞性肺疾病、多发性硬化症和中风。然而，对TREM2功能的机制理解仍然难以捉摸，部分原因是缺乏关于内源性TREM2配体身份的确切信息。虽然已经提出了许多TREM2配体，但其生理作用和结合机制仍有待确定。在这篇综述中，我们强调了TREM2在这些疾病中的假定作用以及我们对TREM2理解的最新进展，并讨论了假定的TREM2-配体相互作用及其在健康和疾病信号传导中的潜在作用。我们基于TREM2结构建立了一个模型，以解释不同的TREM2配体如何与受体相互作用以及疾病风险变体如何改变配体相互作用。最后，我们提出了未来实验方向，以确定这些不同相互作用对TREM2功能的作用和重要性。
