Zhong Li, Zhang Zhen-Lian, Li Xinxiu, Liao Chunyan, Mou Pengfei, Wang Tingting, Wang Zongqi, Wang Zhe, Wei Min, Xu Huaxi, Bu Guojun, Chen Xiao-Fen
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen UniversityXiamen, China.
Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery InstituteLa Jolla, CA, United States.
Front Aging Neurosci. 2017 Jun 21;9:204. doi: 10.3389/fnagi.2017.00204. eCollection 2017.
DNAX-activating protein of 12 kDa (DAP12) is a signaling adapter protein expressed in cells that participate in innate immune responses. By pairing with different triggering receptors expressed on myeloid cell (TREM) proteins, DAP12 can mediate both positive and negative cellular responses. In particular, TREM1 acts as an amplifier of the immune response, while TREM2 functions as a negative regulator. TREM2 has also been shown to stimulate the phagocytosis of apoptotic neurons and define the barrier function in microglia. Notably, loss-of-function mutations of either or result in a disorder known as Nasu-Hakola disease (NHD); and mutations of these genes have been associated with the risk for Alzheimer's disease (AD), suggesting that TREM2 and DAP12 may regulate common signaling pathways in the disease pathogenesis. In this study, we demonstrated an anti-inflammatory role of DAP12 in murine microglia that depends on the presence of TREM2. We also uncovered the JNK signaling pathway as the underlying molecular mechanism by which the TREM2/DAP12 complex suppresses the hyperactivation of microglia upon LPS stimulation. Interestingly, LPS down-regulates the expression of via the activation of JNK and NF-κB signaling pathways, resulting in a vicious cycle that synergistically promotes the inflammatory responses. Our study provides insights into mechanism-based therapy for neuroinflammatory disorders.
12千道尔顿DNAX激活蛋白（DAP12）是一种信号衔接蛋白，在参与先天性免疫反应的细胞中表达。通过与髓系细胞表达的不同触发受体（TREM）蛋白配对，DAP12可以介导细胞的正负反应。特别是，TREM1作为免疫反应的放大器，而TREM2则作为负调节因子发挥作用。TREM2还被证明可以刺激凋亡神经元的吞噬作用，并确定小胶质细胞中的屏障功能。值得注意的是，TREM2或DAP12的功能丧失突变会导致一种名为纳苏-哈科拉病（NHD）的疾病；并且这些基因的突变与阿尔茨海默病（AD）的风险相关，这表明TREM2和DAP12可能在疾病发病机制中调节共同的信号通路。在本研究中，我们证明了DAP12在小鼠小胶质细胞中的抗炎作用依赖于TREM2的存在。我们还发现JNK信号通路是TREM2/DAP12复合物在LPS刺激下抑制小胶质细胞过度激活的潜在分子机制。有趣的是，LPS通过激活JNK和NF-κB信号通路下调DAP12的表达，导致恶性循环，协同促进炎症反应。我们的研究为基于机制的神经炎症性疾病治疗提供了见解。
