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Sphingosine-1-phosphate,a novel trem2 ligand,promotes microglial phagocytosis to protect against ischemic brain injury

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1885-1898页

作者： Tengfei Xue Juan Ji Yuqin Sun Xinxin Huang Zhenyu Cai Jin Yang Wei Guo Ruobing Guo Hong Cheng Xiulan Sun Department of Pharmacology Neuroprotective Drug Discovery Key LaboratoryJiangsu Key Laboratory of NeurodegenerationNanjing Medical UniversityNanjing 211166China Nanjing University of Chinese Medicine the Affiliated Hospital of Nanjing University of Chinese MedicineNanjing 210004China The First Affiliated Hospital of Nanjing Medical University Nanjing 210029China

The mechanism of sphingosine-1-phosphate(S1P)-mediated phagocytosis remains ***,we found that S1P or FTY720(an analog of S1P)promoted microglial phagocytosis in stroke independent of ***,we used computer simulation of molecular docking to predict that S1P might be a ligand for triggering receptor expressed on myeloid cells 2(trem2).Next,microscale thermophoresis(MST),surface plasmon resonance(SPR)and liquid chromatography–tandem mass spectrometry(LC–MS/MS)were performed to reveal that S1P was a novel trem2 ***,we confirmed the pro-phagocytosis of S1P targeting in trem2-Dap12 transfected CHO cells and trem2 knockdown *** mutation analysis showed that D104 was the critical binding ***2^(−/−)mice were used to demonstrate the role of S1P-induced phagocytosis targeting on trem2 in protecting against ischemic brain ***,further studies revealed that apolipoprotein E(APOE)loaded with S1P was released by microglia and bound to apoptotic neurons via LDL receptor related protein 1B(LRP1B)and thereby induced microglia to phagocytose apoptotic ***,the present work reveals for the first time that S1P acts as a novel endogenous ligand of trem2 to effectively promote microglial *** findings provide a new lead compound for developing immunomodulator targeting on trem2.

关键词： S1P trem2 Microglia Phagocytosis Stroke APOE LRP1B Apoptotic neurons

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Up-Regulation of trem2 Inhibits Hippocampal Neuronal Apoptosis and Alleviates Oxidative Stress in Epilepsy via the PI3K/Akt Pathway in Mice

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Neuroscience Bulletin 2019年第3期35卷 471-485页

作者： Ai-Hua Liu Min Chu Yu-Ping Wang Department of Neurology Xuanwu Hospital Capital Medical University

Epilepsy is a chronic and severe neurological disorder that has negative effects on the autonomous activities of patients. Functionally, trem2(triggering receptor expressed on myeloid cells-2) is an immunoglobulin receptor that affects neurological and psychiatric genetic diseases. Based on this rationale, we aimed to assess the potential role of trem2 integration with the PI3 K/Akt pathway in epilepsy. We used microarray-based gene expression profiling to identify epilepsy-related differentially-expressed genes. In a mouse hippocampal neuron model of epilepsy, neurons were treated with lowMg^2+ extracellular fluid, and the protein and mRNA expression of trem2 were determined. Using a gain-offunction approach with trem2, neuronal apoptosis and its related factors were assessed by flow cytometry, RT-qPCR,and Western blot analysis. In a pilocarpine-induced epileptic mouse model, the malondialdehyde(MDA) and8-hydroxy-20-deoxyguanosine(8-OHdG) content and superoxide dismutase(SOD) and glutathione-peroxidase(GSH-Px) activity in the hippocampus were determined,and the protein expression of trem2 was measured. In addition, the regulatory effect of trem2 on the PI3 K/Akt pathway was analyzed by inhibiting this pathway in both the cell and mouse models of epilepsy. trem2 was found to occupy a core position and was correlated with ***2 was decreased in the hippocampus of epileptic miceand epileptic hippocampal neurons. Of crucial importance,overexpression of trem2 activated the PI3 K/Akt pathway to inhibit neuronal apoptosis. Moreover, activation of the PI3 K/Akt pathway through over-expression of trem2 alleviated oxidative stress, as shown by the increased expression of SOD and GSH-Px and the decreased expression of MDA and 8-OHdG. The current study defines the potential role of trem2 in inhibiting the development of epilepsy, indicating that trem2 up-regulation alleviates hippocampal neuronal injury and oxidative stress, and inhibits neuronal apoptosis in epilepsy

关键词： trem2 Epilepsy Neuronal apoptosis PI3K/Akt pathway Oxidative stress

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Hippocampal overexpression of trem2 ameliorates high fat diet induced cognitive impairment and modulates phenotypic polarization of the microglia

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Genes & Diseases 2022年第2期9卷 401-414页

作者： Min Wu Maolin Liao Rongfeng Huang Chunxiu Chen Tian Tian Hongying Wang Jiayu Li Jibin Li Yuxiang Sun Chaodong Wu Qifu Li Xiaoqiu Xiao Department of Endocrinology The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016PR China The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016PR China Department of Nutrition and Food Hygiene School of Public Health and ManagementChongqing Medical UniversityChongqing 400016PR China Department of Neurology Affiliated Hospital of Guizhou Medical UniversityGuiyangGuizhou 550004PR China Department of Nutrition and Food Science Texas A&M UniversityCollege StationTX 77843USA

Type 2 diabetes mellitus(T2DM)and Alzheimer's disease(AD)share several common pathophysiological *** variants of triggering receptor expressed on myeloid cells 2(trem2)increase the risk of developing AD,suggesting the involvement of trem2 and innate immunity in AD *** is still unknown whether trem2 is related to cognitive impairment in ***,we investigated the effects of the hippocampal overexpression of trem2 on cognitive in long-term high-fat diet(HFD)-fed *** C57BL/6J mice were maintained on HFD for 50 ***2 was overexpressed in the hippocampus 36 weeks after HFD feeding using adeno-associated virus vector(AAV)-mediated gene *** results showed that the HFD feeding induced rapid and persistent weight gain,glucose intolerance and significant impairments in learning and *** with AAV-con,AAV-trem2 significantly ameliorated cognitive impairment without altering body weight and glucose homeostasis in HFD *** overexpression of trem2 upregulated the synaptic proteins spinophilin,PSD95 and synaptophysin,suggesting the improvement in synaptic *** complexity and spine density in the CA1 region were rescued after trem2 ***,trem2 markedly increased the number of iba-1/Arg-1-positive microglia in the hippocampus,suppressed neuroinflammation and microglial *** sum,hippocampal trem2 plays an important role in improving HFD-induced cognitive dysfunction and promoting microglial polarization towards the M2 anti-inflammatory *** study also suggests that trem2 might be a novel target for the intervention of obesity/diabetes-associated cognitive decline.

关键词： Diabetes Microglial polarization Neurodegeneration Neuroinflammation Obesity trem2

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trem2在阿尔兹海默症中的研究进展

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中国药理学通报 2020年第8期36卷 1049-1053页

作者：李晓月倪赛佳姚增莹张启春南京中医药大学药学院江苏南京210023

小胶质细胞是中枢神经系统(central nervous system,CNS)中发挥主要免疫作用的细胞,近年来,大量研究表明其对于健康状态下脑稳态的维持及神经系统疾病发展均发挥重要作用。髓系细胞触发受体2(triggering receptor expressed on myeloidc... 详细信息

小胶质细胞是中枢神经系统(central nervous system,CNS)中发挥主要免疫作用的细胞,近年来,大量研究表明其对于健康状态下脑稳态的维持及神经系统疾病发展均发挥重要作用。髓系细胞触发受体2(triggering receptor expressed on myeloidcells 2,trem2)是一种在脑组织中仅表达于小胶质细胞的单程跨膜受体。最初发现trem2的失活突变与Nasu-Hakola(NHD)的发生相关,而在发现trem2编码点单核苷酸多态性(single nucleotidepolymorphisms,SNPs)可显著增加阿尔兹海默症发病风险后则更受关注。该文就trem2结构、功能,及其与阿尔兹海默症等中枢神经系统疾病的关联性进行分析,探讨trem2在维持中枢神经系统健康状态中的作用及其作为脑疾病治疗靶点的可能。

关键词： trem2 单个核苷酸多态性小胶质细胞神经系统疾病神经炎症阿尔兹海默症

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trem2基因的敲低加重纳米氧化铝导致的神经发育障碍

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生态毒理学报 2022年第4期17卷 164-174页

作者：郭馨岳赵锦津高晓诚张兰黄涛王艳红牛侨张勤丽山西医科大学公共卫生学院劳动卫生教研室太原030001

纳米氧化铝(alumina nanoparticles,AlNPs)作为一种新的纳米科技材料被广泛应用,其潜在的毒性也被广泛研究。Ⅱ型髓系细胞触发受体(triggering receptor expressed on myeloid cells 2,trem2)高度特异表达于中枢神经系统内的小胶质细胞... 详细信息

纳米氧化铝(alumina nanoparticles,AlNPs)作为一种新的纳米科技材料被广泛应用,其潜在的毒性也被广泛研究。Ⅱ型髓系细胞触发受体(triggering receptor expressed on myeloid cells 2,trem2)高度特异表达于中枢神经系统内的小胶质细胞,对脑稳态的维持及神经系统疾病发展均发挥着重要作用。为了探究trem2基因在AlNPs致神经发育障碍中的作用,将6 hpf(hours post-fertilization)的斑马鱼胚胎分为对照组(control)、阴性对照组(negative con)、trem2敲低组(trem2-)、纳米氧化铝组(AlNPs)、trem2敲低+纳米氧化铝组(trem2-/+AlNPs)。在受精1 h内用显微注射技术敲低trem2基因,并染毒144 h。染毒结束后对各组进行形态学和生殖毒性观察;用运动轨迹跟踪仪记录斑马鱼的行为轨迹。检测trem2基因、神经发育基因α1-tubulin、mbp和syn2a的表达量;以及神经递质和氧化应激情况。结果发现,各组幼鱼在死亡率、孵化率和畸形率方面无显著差异(P>0.05)。运动行为检测发现,trem2-组、AlNPs组、trem2-/+AlNPs组幼鱼在黑暗状态下的平均速度、移动距离、外圈停留时间百分比显著降低而绝对转角增大(Ptrem2-/+AlNPs组有明显的惊恐逃避反射(Ptrem2-组、AlNPs组和trem2-/+AlNPs组的神经发育相关基因α1-tubulin、mbp和syn2a,乙酰胆碱酯酶(acetylcholinesterase,AChE)活性以及超氧化物歧化酶(superoxide dismutase,SOD)活性显著降低(Ptrem2基因会加重AlNPs导致的神经发育毒性,进一步说明trem2基因在神经发育中的重要作用。

关键词：纳米氧化铝斑马鱼神经毒性 trem2 神经发育

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trem2介导小胶质细胞吞噬功能在神经退行性疾病中的作用

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中国免疫学杂志 2022年第11期38卷 1388-1394页

作者：韩雪夏天娇刘斌文顾小萍(指导) 南京大学医学院附属鼓楼医院麻醉科南京210008 南京大学江苏省分子医学重点实验室南京210093

以阿尔茨海默病(AD)为代表的多种慢性神经退行性疾病发病机制尚未明确。近年研究发现神经退行性疾病发生与错误折叠的蛋白质、淀粉样蛋白(Aβ)、死亡神经元和受损髓鞘吞噬清除障碍有关,而完整的小胶质细胞吞噬功能是维持中枢神经系统稳... 详细信息

以阿尔茨海默病(AD)为代表的多种慢性神经退行性疾病发病机制尚未明确。近年研究发现神经退行性疾病发生与错误折叠的蛋白质、淀粉样蛋白(Aβ)、死亡神经元和受损髓鞘吞噬清除障碍有关,而完整的小胶质细胞吞噬功能是维持中枢神经系统稳态的重要原因。小胶质细胞表面吞噬受体髓样细胞触发受体2(trem2)表达改变可调节小胶质细胞吞噬效率,负性调节TLR诱导的炎症反应,促进M2小胶质细胞表型表达,发挥神经保护作用。此外,trem2功能突变对小胶质细胞吞噬功能的影响与AD、帕金森病等神经退行性疾病风险增加相关。因此,了解trem2介导的小胶质细胞吞噬清除功能在不同神经退行性疾病中的作用对于探索神经退行性疾病新的治疗方向具有重要意义。

关键词： trem2 trem2变体小胶质细胞吞噬神经退行性疾病

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trem2 deficiency exacerbates insulin resistance via promoting inflammatory response of adipose tissue macrophages

TREM2 deficiency exacerbates insulin resistance via promotin...

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浙江省免疫学会第六次会员代表大会暨第十一次学术大会

作者： Can Liu Pinhao Li Hui Li Sicong Wang Lifeng Ding Hanbin Wang Jinchao Hou Xiangming Fang Qiang Shu School of Medicine Zhejiang University

Background:Adipose tissue macrophage(ATM)plays a significant role in obesity-induced insulin resistance(IR).Recent studies reported that down-regulation of trigger receptor expressed on myeloid cells 2(trem2)in adipose tissue is closely associated with advanced IR in patients with ***:This study aims to investigate whether trem2 deficiency will exacerbate IR via promoting ATM inflammatory response in obese ***:Macrophages from wild type(WT)mice were stimulated with free fatty acids(FFA)for12 hours,and trem2 expression was *** the in vivo study,trem2 knock out(KO)and WT mice were fed with a high fat diet(HFD)for 12 *** and adipose tissue inflammation were ***,pro-inflammatory cytokines were measured in macrophages from trem2 KO and WT mice which were both stimulated with ***:Macrophage trem2 was down-regulated in response to FFA stimulation ex ***2 KO mice had increased body weight,elevated adipose tissue inflammation and deteriorated IR under HFD *** from trem2 KO mice also expressed more pro-inflammatory ***,trem2 deficiency augmented macrophage inflammatory response under FFA ***:trem2 deficiency promotes adipose tissue inflammation,and ATM inflammatory response,resulting in deterioration of IR in obese mice.

关键词： trem2 obesity insulin resistance adipose tissue macrophage

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黄芩苷通过trem2/TLR4/NF-κB信号通路抑制脂多糖/干扰素γ诱导的BV2细胞炎症反应

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中国中药杂志 2022年第6期47卷 1603-1610页

作者：贺春香于文静杨苗李泽夏小芳李平成绍武宋祯彦湖南中医药大学中西医结合心脑疾病防治湖南省重点实验室湖南长沙410208

基于2型髓样细胞触发受体(triggering receptor expressed on myeloid cells 2,trem2)/Toll样受体4(Toll-like receptor 4,TLR4)/核因子κB(nuclear factor kappaB,NF-κB)信号通路,探讨黄芩苷对脂多糖(LPS)/干扰素γ(IFN-γ)诱导的小胶质细胞炎性活化的作用机制。通过LPS联合IFN-γ干预构建小鼠小胶质细胞(BV2)炎性活化模型,分为正常组、模型组、黄芩苷低剂量组(5μmol·L^(-1))、黄芩苷中剂量组(10μmol·L^(-1))、黄芩苷高剂量组(20μmol·L^(-1))和米诺环素组(10μmol·L^(-1))。CCK-8检测细胞存活率;明场下观察细胞形态;实时荧光定量PCR(quantitative real-time PCR,qPCR)法检测白细胞介素-1β(interleukin-1β,IL-1β)、白细胞介素-4(interleukin-4,IL-4)、诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)、白细胞介素-6(interleukin-6,IL-6)、白细胞介素-10(interleukin-10,IL-10)和精氨酸酶-1(arginase-1,Arg-1)mRNA表达;Western blot法检测肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、IL-1β、trem2、TLR4、核因子抑制蛋白(inhibitor kappaB alpha,IκBα)、p-IκBα、NF-κB p65、p-NF-κB p65蛋白表达水平;细胞免疫荧光检测NF-κB p65的入核情况。与空白组比较,模型组BV2细胞大多数趋向于促炎症的M1阿米巴形态,IL-1β、IL-6和iNOS mRNA水平显著升高,IL-4、IL-10和Arg-1 mRNA水平显著降低(Ptrem2蛋白表达水平下降,核内NF-κB p65表达升高;与模型组比较,黄芩苷和米诺环素干预各组BV2细胞形态呈现不同程度的恢复,IL-1β、IL-6和iNOS mRNA水平均明显降低,IL-4、IL-10和Arg-1 mRNA水平升高(Ptrem2蛋白表达水平升高,核内NF-κB p65的表达降低。以上结果表明,黄芩苷可以通过调节小胶质细胞trem2-TLR4之间的失衡,抑制下游NF-κB激活,从而促进小胶质细胞从促炎表型向抗炎表型的极化。

关键词：小胶质细胞黄芩苷 trem2 TLR4 NF-κB 炎症反应

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trem2/β-catenin attenuates macrophage pyroptosis to promote bacterial eradication of Pseudomonas aeruginosa

TREM2/β-catenin attenuates macrophage pyroptosis to promote...

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第十三届全国免疫学学术大会

作者： Minhao Wu Yi Wang Yiting Liu Siping Liang Qiaojuan Liu Sun Yat-sen University Zhongshan School of Medicine

Triggering receptors expressed on myeloid cells 2(trem2) is a cell surface receptor mainly found on macrophages. It is reported that trem2 inhibits inflammatory responses, but promotes bacterial clearance during in vivo and in vitro infections with Pseudomonas aeruginosa(PA). However, the underlying mechanism remains unclear. Our study demonstrated that trem2 deficiency or knockdown significantly enhanced PA-induced macrophage pyroptosis, a novel form of pro-inflammatory programmed cell death, which is induced by infectious or inflammatory stimuli and characterized by the cleavage of Caspase-1 and gasdermin D(GSDMD). Blockage of pyroptosis by knocking out/down Caspase-1 or silencing GSDMD enhanced macrophage-mediated bacterial killing of PA. While treatment with Caspase-1 inhibitor(YVAD) relieved trem2 deficiency-mediated suppression of PA clearance. In addition, we found that trem2 activated β-catenin signaling pathway via promoting its phosphorylation at S675 and enhancing the protein stability. Moreover, silencing of β-catenin enhanced pyroptotic cell death but impaired macrophage-mediated clearance of PA, while overexpression of β-catenin inhibited Caspase-1-dependent pyroptosis, and thereby restored cell survival and bacterial elimination in trem2-silenced macrophages. Notably, in vitro studies suggested that trem2/β-catenin suppressed the activation of NLRP3 and NLRC4 inflammasomes in macrophages challenged with PA or specific inflammasome activators. Collectively, our study provides a novel mechanism of trem2-mediated antibacterial immunity and explores the relationship between pyroptosis and bacterial eradication.

关键词： trem2 β-catenin bacteria macrophage pyroptosis

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小胶质细胞trem2调控阿尔茨海默病发生的机制研究进展

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生命科学 2023年第11期35卷 1484-1497页

作者：姜敏艳汪旭郭锡汉云南师范大学生命科学学院生物能源持续开发与利用教育部工程研究中心昆明650500 台州耶大基因与细胞治疗研究院台州318000

阿尔茨海默病(AD)是最常见的一种神经退行性疾病,具有多因异质性的特点,具体致病原因尚不清晰。小胶质细胞是常驻于中枢神经系统中的巨噬细胞,负责细胞吞噬、突触修剪、能量代谢等。髓系细胞触发受体2(trem2)是一种主要存在于小胶质细... 详细信息

阿尔茨海默病(AD)是最常见的一种神经退行性疾病,具有多因异质性的特点,具体致病原因尚不清晰。小胶质细胞是常驻于中枢神经系统中的巨噬细胞,负责细胞吞噬、突触修剪、能量代谢等。髓系细胞触发受体2(trem2)是一种主要存在于小胶质细胞表面的受体,对小胶质细胞的功能稳态至关重要。trem2 R47H和R62H两个变异体会增加个体晚发性AD风险,该发现使trem2成为AD领域一个新的研究热点。本文主要围绕小胶质细胞trem2的结构、表达调控、信号转导、功能及其在AD中的病理学作用等多个方面进行系统性综述,以期在加深理解trem2的同时,为深入研究小胶质细胞trem2表达和功能异常在AD发生发展中的作用和分子机制提供参考。

关键词：小胶质细胞阿尔茨海默病 trem2 Aβ Tau

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