Soluble TREM2 induces inflammatory responses and enhances microglial survival.
Soluble TREM2 induces inflammatory responses and enhances microglial survival.
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可溶性 TREM2 会诱导炎症反应并增强小胶质细胞的存活。
DOI：
10.1084/jem.20160844
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发表时间：
2017-03-06
期刊：
影响因子：
--
通讯作者：
Bu G
中科院分区：
文献类型：
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作者：
Zhong L;Chen XF;Wang T;Wang Z;Liao C;Wang Z;Huang R;Wang D;Li X;Wu L;Jia L;Zheng H;Painter M;Atagi Y;Liu CC;Zhang YW;Fryer JD;Xu H;Bu G
Zhong等人描述了可溶性TREM 2（sTREM 2）在小胶质细胞中调节促炎反应和预防细胞凋亡的两种新作用。髓样细胞上表达的触发受体2（TREM 2）是在脑中的小胶质细胞中表达的先天性免疫受体。来源于细胞表面受体的蛋白水解裂解的可溶形式的TREM 2（sTREM 2）在AD的临床前阶段中增加，并且与脑脊液中的总tau和磷酸化tau的量正相关。然而，sTREM 2的生理和病理功能仍然未知。在这里，我们发现sTREM 2以PI 3 K/Akt依赖的方式促进小胶质细胞存活，并刺激依赖于NF-κB的炎性细胞因子的产生。携带AD风险相关突变的sTREM 2变体在抑制细胞凋亡和触发炎症反应方面的效力较低。重要的是，sTREM 2传递到野生型和Trem 2敲除小鼠的小脑顶，升高了炎性细胞因子的表达，并诱导了小胶质细胞的形态学变化。总的来说，这些数据表明sTREM 2触发小胶质细胞活化，诱导炎症反应并促进存活。本研究对AD的发病机制有一定的启示，并为靶向sTREM 2通路治疗AD提供了新的思路。
Zhong et al. describe two novel roles for soluble TREM2 (sTREM2) in regulation of proinflammatory responses and prevention of cellular apoptosis in microglia. Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed in microglia in the brain. A soluble form of TREM2 (sTREM2) derived from proteolytic cleavage of the cell surface receptor is increased in the preclinical stages of AD and positively correlates with the amounts of total and phosphorylated tau in the cerebrospinal fluid. However, the physiological and pathological functions of sTREM2 remain unknown. Here, we show that sTREM2 promotes microglial survival in a PI3K/Akt-dependent manner and stimulates the production of inflammatory cytokines depending on NF-κB. Variants of sTREM2 carrying AD risk-associated mutations were less potent in both suppressing apoptosis and triggering inflammatory responses. Importantly, sTREM2 delivered to the hippocampi of both wild-type and Trem2-knockout mice elevated the expression of inflammatory cytokines and induced morphological changes of microglia. Collectively, these data indicate that sTREM2 triggers microglial activation inducing inflammatory responses and promoting survival. This study has implications for the pathogenesis of AD and provides insights into targeting sTREM2 pathway for AD therapy.