髓样细胞触发性受体-1基础研究与临床应用

髓样细胞触发性受体-1（triggering receptor expressed on myeloid cells-1,TREM-1）是表达于中性粒细胞、单核细胞与巨噬细胞表面的免疫球蛋白家族胞膜受体。有研究显示,TREM-1能够放大模式识别受体介导的炎性反应,在全身炎性反应综合征（SIRS）中发挥重要作用。TREM．1在慢性炎性活动期、恶性肿瘤等病理过程中也有不同程度上凋。以TREM-1为靶点的靶向药物有望对上述疾病治疗产生重大影响。同时,游离型TREM-1（soluble TREM-1,sTREM-1）可作为判断多种疾病预后的重要指标。     

髓系细胞触发受体-1在脂多糖急性肺损伤大鼠肺组织中的表达及其与内质网应激和炎性反应的关系

目的:研究髓系细胞触发受体-1(TREM-1)在脂多糖急性肺损伤(ALI)大鼠肺组织中的表达及其与内质网应激和炎性反应的关系。方法:选择成年雄性SD大鼠100只作为研究对象,将其分成ALI组(n=60)、对照1组(n=15)、观察组(n=20)和对照2组(n=5)。对比ALI组和对照1组TREM-1、内质网应激表达及肿瘤坏死因子-α(TNF-α)水平、Smith评分,对比观察组和对照2组的CHOP mRNA、GRP mRNA表达情况,并分析TREM-1与内质网应激、炎性反应和Smith评分的相关性。结果:ALI组6h、12h、1d及2d时间点的TREM-1 mRNA、CHOP mRNA、GRP78 mRNA、TREM-1、TNF-α水平及Smith评分均高于对照1组,且ALI组随着时间的推移,TREM-1 mRNA、CHOP mRNA、GRP78 mRNA、TREM-1、TNF-α水平及Smith评分均呈升高的趋势,在1d时达到最高,然后呈下降趋势(P0.05)。观察组6h、12h、1d及2d时间点的CHOP mRNA、GRP mRNA表达高于对照2组,且观察组随着时间的推移CHOP mRNA、GRP mRNA表达均呈升高的趋势,在1d时达到最高,然后呈下降趋势(P0.05)。根据Spearman法分析相关性发现,TREM-1 mRNA及TREM-1水平均与CHOP mRNA、GRP78 mRNA及Smith评分呈正相关,且TREM-1水平与TNF-α呈正相关(P0.05)。结论:TREM-1在脂多糖ALT大鼠肺组织中的表达较高,且参与ALT肺部炎性反应,激活TREM-1可增强巨噬细胞内质网应激。     

综述:髓系衍生的抑制性细胞与肿瘤免疫耐受关系的研究进展

髓系衍生的抑制性细胞(myeloid-derived suppressor cells,MDSCs),是在肿瘤等病理因素的作用下髓系细胞发生分化障碍所产生的不同阶段髓系祖细胞的集合,具有广谱而强大的免疫抑制功能,是免疫系统的重要负性调节组件之一.研究表明:肿瘤微环境中的多种细胞因子或生长因子可通过激活相应的信号通路促进MDSCs扩增及活化,MDSCs进而通过多种机制抑制包括T细胞在内的多种免疫细胞的功能而促进肿瘤个体免疫耐受的发生.临床研究表明:肿瘤患者体内MDSCs的水平与肿瘤临床病程进展密切相关,基于MDSCs的免疫治疗也有望成为肿瘤免疫治疗的新策略.本文主要介绍了肿瘤中MDSCs的表型鉴定、扩增及活化机制、发挥免疫抑制作用的途径及机制、肿瘤中MDSCs的临床意义以及本领域需要解决的问题,以期对MDSCs在肿瘤免疫耐受中的作用进展提供参考.     

髓系抑制细胞在1型糖尿病患者中作用的研究

髓系抑制细胞(myeloid-derived suppressor cells, MDSC)是来源于髓系的一类未成熟细胞群,初期对肿瘤的研究中发现,这类细胞具有抑制免疫应答,并促进炎性细胞因子及趋化因子分泌的作用,近年来对这类细胞在治疗自身免疫性疾病等方面的作用进行了研究。发现MDSC具有治疗自身免疫性疾病的功效;但也有研究显示,MDSC不仅无治疗效果,甚至还会起到相反的作用,这可能与其促炎因子过度分泌或诱导辅助性T细胞17(T helper cell, Th17)分化有关。1型糖尿病(type 1 diabetes, T1D)是一种常见的自身免疫性疾病,如何有效治疗该疾病一直是内分泌研究领域的热点。现就MDSC的来源、功能及其在T1D中的作用进行阐述,旨在为T1D的治疗提供新思路。     

脓毒症患者中可溶性髓样细胞触发受体1、降钙素原、核因子κB水平与肠道菌群失调的相关性

本研究旨在探讨脓毒症患者中血清可溶性髓样细胞触发受体1(soluble myeloid cell trigger receptor 1,sTREM1)、降钙素原(procalcitonin,PCT)、核因子κB(nuclear factor­κB,NF­κB)水平与肠道菌群失衡的相关性。将2016年5月-2019年6月重庆市綦江区人民医院消化内科收治的86例脓毒症患者纳入脓毒症组,同期收治的未并发脓毒症患者50例纳入非脓毒症组,同期到本院进行体检的健康人50例纳入对照组,比较3组之间肠道菌群α多样性、肠道菌群含量,以及血清sTREM1、PCT、NF­κB水平的差异,并进行Spearman相关性分析。结果显示,脓毒症组Ace指数、Chao指数、Shannon指数显著低于非脓毒症组和对照组,Simpson指数显著高于非脓毒症组和对照组(P<0.05);脓毒症组类杆菌、双歧杆菌含量显著低于非脓毒症组和对照组,肠球菌、大肠埃希菌、葡萄球菌含量显著高于非脓毒症组和对照组(P<0.05);脓毒症组血清sTREM1、PCT、NF­κB水平显著高于非脓毒症组和对照组(P<0.05)。Spearman相关性分析显示,脓毒症患者中sTREM1、PCT、NF­κB水平与Ace指数、Chao指数、Shannon指数均呈负相关(P<0.05),与Simpson指数呈正相关(P<0.05)。结果提示,脓毒症患者中血清sTREM1、PCT、NF­κB水平与肠道菌群失衡有关联。     

髓系单核细胞来源的HIV-1限制性因子——SAMHD1

天然抗病毒限制因子是HIV-1研究最热点的领域。继APOBEC3G、Trim5α、Tetherin被发现之后,SAMHD1于2011年被发现为新的抗HIV-1限制因子。它主要在髓系来源的单核细胞中表达,如巨噬细胞和树突状细胞。该文对SAMHD1的结构、抗病毒机制、与Vpx的相互作用以及进化等方面的研究进行了综述。SAMHD1的发现为深入研究SAMHD1在慢病毒致病机理中作用打开了一扇门。     

甲酰肽受体研究进展

趋化剂N-甲酰肽,如fMLF(N-甲酰甲硫氨酰-亮氨酰-苯丙氨酸)与受体结合后,能在炎症和免疫应急反应时募集嗜中性粒细胞游走和聚集在病灶处,对抗并清除病原微生物。近年来发现的许多结构各异的非N-甲酰肽配体(包括炎症早期出现的内源性多肽)均具有趋化和激活噬菌性白细胞的作用。这些研究进展拓展了我们对甲酰肽受体功能的认识,同时也提出一系列新问题,值得深入探讨。     

细菌性血流感染所致脓毒症患者血清PCT、APOM、sTREM-1与预后的关系研究

摘要 目的：探讨细菌性血流感染（BSI）所致脓毒症患者血清降钙素原（PCT）、载脂蛋白M（APOM）、可溶性髓系细胞触发受体-1（sTREM-1）与预后的关系。方法：选取2021年1月～2023年10月首都医科大学附属北京朝阳医院收治的细菌性BSI所致脓毒症患者185例（脓毒症组）,根据28d内预后情况分为死亡组（61例）和存活组（124例）,另选取同期体检健康志愿者87例（对照组）。采用电化学发光法检测血清PCT水平,酶联免疫吸附法检测血清APOM、sTREM-1水平。单因素及多因素Logistic回归模型分析影响细菌性BSI所致脓毒症患者预后的因素。受试者工作特征（ROC）曲线分析血清PCT、APOM、sTREM-1对细菌性BSI所致脓毒症患者预后的预测价值。结果：与对照组比较,脓毒症组血清PCT、sTREM-1水平升高,APOM水平降低（P＜0.05）。185例细菌性BSI所致脓毒症患者28d死亡死亡率为32.97%（61/185）。与存活组比较,死亡组血清PCT、sTREM-1水平升高,APOM水平降低（P＜0.05）。多因素分析结果显示：革兰阴性菌感染、脓毒性休克、中性粒细胞/淋巴细胞比值（NLR）升高、序贯器官衰竭评估（SOFA）评分增加、急性生理和慢性健康评估Ⅱ（APACHEⅡ）评分增加、血清PCT升高和sTREM-1升高为细菌性BSI所致脓毒症患者死亡的独立危险因素,血清APOM升高为独立保护因素（P＜0.05）。血清PCT、APOM、sTREM-1联合检测预测细菌性BSI所致脓毒症患者死亡的曲线下面积为0.908,大于血清PCT、APOM、sTREM-1单独检测预测的0.785、0.779、0.783。结论：细菌性BSI所致脓毒症患者血清PCT、sTREM-1水平升高和APOM水平降低与预后不良的发生有关,血清PCT、APOM、sTREM-1联合检测对细菌性BSI所致脓毒症患者死亡有较高的预测价值。     

胰高血糖素样肽-1与受体相互作用研究进展

胰高血糖素样肽-1(GLP-1)具有促胰岛素分泌、抑制胰高血糖素分泌、刺激胰岛β细胞的增殖和分化、抑制β细胞凋亡、抑制胃排空等作用,近年来成为治疗糖尿病药物研究中的热点。GLP-1与受体的相互作用一直备受关注,我们从4个方面对GLP-1与受体相互作用的研究进行了综述:GLP-1的二级结构、GLP-1单个残基改变及残基间的相互作用、GLP-1不同残基片段对GLP-1结合并激活受体的影响和GLP-1受体的相互作用模式。     

Expression and Purification of a Functional Porcine Soluble Triggering Receptor Expressed on Myeloid Cells 1

Triggering receptor expressed on myeloid cells 1 (TREM-1) plays a vital role in the pathogen-triggered amplification loop required for proinflammatory responses. Blockade of TREM-1 signaling may inhibit expansion of sepsis and prolong survival of animals. In the present study, the gene of porcine soluble TREM-1 was cloned and expressed in E. coli. After purification, the bioactivity of recombinant porcine soluble TREM-1 was tested in vitro on porcine alveolar macrophages. The results showed that supplementation with the recombinant porcine sTREM-1 protein rapidly and dose-dependently attenuated the upregulation of cytokines (IL-1β, IL-2, IL-4, IL-8, IL-10, IL-12, IL-16, IL-18, and TNF-α) caused by LPS stimulation in the cultured porcine alveolar macrophages. These results indicate that the recombinant porcine sTREM-1 protein can prevent TREM-1-mediated hyperinflammatory responses after exposure to LPS.     

sTREM-1、PCT在社区获得性肺炎早期诊断中的价值

目的:探讨可溶性髓系细胞触发受体-1(soluble triggeringreceptorexpressed on myeloidcells-1,sTREM-1)、降钙素原(procalcitonin,PCT)在社区获得性肺炎(community-acquired pneumonia,CAP)早期诊断中的价值。方法:选择48例CAP住院患者(其中重症肺炎8例)和病毒性上呼吸道感染患者20例,所有病例均在入院后24小时内取血清,采用酶联免疫测定法(ELISA法)测定其血清sTREM-1、PCT水平,并应用受试者工作特征曲线(receiver operating characteristic curve,ROC曲线)分析二者对CAP的诊断价值。结果:入院后24小时内,普通肺炎患者、重症肺炎患者血清sTREM-1、PCT水平均明显高于对照组,且重症肺炎组明显高于普通肺炎组,差异均具有统计学意义(P0.01)。二者诊断CAP的ROC曲线下面积分别为0.884、0.788,联合二者诊断CAP的ROC曲线下面积为0.921。结论:sTREM-1、PCT均可作为CAP早期诊断有价值的参考标志物,sTREM-1比PCT更有参考价值,联合检测血清sTREM-1、PCT水平对CAP的早期诊断价值高于单一指标。     

Prospective Evaluation of Procalcitonin,Soluble Triggering Receptor Expressed on Myeloid Cells-1 and C-Reactive Protein in Febrile Patients with Autoimmune Diseases

BackgroundBoth procalcitonin (PCT) and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) have been investigated separately as indicators of infection in patients with autoimmune diseases. Our study simultaneously evaluated both PCT and sTREM-1 along with C-reactive protein (CRP) in febrile patients with autoimmune diseases.MethodsFifty-nine patients were enrolled in the study. The patients were categorized into the infection group (n = 24) or the disease flare group (n = 35). sTREM-1, PCT and CRP concentrations at fever onset were compared between the two groups of patients.ResultssTREM-1 and CRP did not differ between the two groups. PCT [median (range), ng/ml] was higher in the infection group than in the disease flare group [0.53 (0.02–12.85) vs. 0.12 (0.02–19.23), p = 0.001]. The area under the receiver-operating characteristic (ROC) for diagnosis of infection was 0.75 for PCT (p = 0.001), 0.63 for CRP (p = 0.09) and 0.52 for sTREM-1 (p = 0.79). Using 0.2 ng/ml as the cutoff value for PCT, sensitivity was 0.75 and specificity was 0.77. Negative predictive values for PCT were 92%, 87% and 82% for a prevalence of infection of 20%, 30%, and 40%, respectively. Neither immunosuppressants nor biomodulators affected the level of the three biomarkers. However, in patients treated with corticosteroids, the levels of sTREM-1 and CRP were significantly decreased compared with the untreated patients.ConclusionsSetting PCT at a lower cutoff value could provide useful information on excluding infection in febrile patients with autoimmune diseases. The possible effect of corticosteroids on the level of sTREM-1 as an infection marker deserves further study.     

The Triggering Receptor Expressed on Myeloid Cells 2 Binds Apolipoprotein E

The triggering receptor expressed on myeloid cells 2 (TREM2) is an Ig-like V-type receptor expressed by populations of myeloid cells in the central nervous system and periphery. Loss-of-function mutations in TREM2 cause a progressive, fatal neurodegenerative disorder called Nasu-Hakola disease. In addition, a TREM2 R47H coding variant was recently identified as a risk factor for late-onset Alzheimer disease. TREM2 binds various polyanionic molecules but no specific protein ligands have been identified. Here we show that TREM2 specifically binds apolipoprotein E, a well established participant in Alzheimer disease. TREM2-Ig fusions efficiently precipitate ApoE from cerebrospinal fluid and serum. TREM2 also binds recombinant ApoE in solution and immobilized ApoE as detected by ELISA. Furthermore, the Alzheimer disease-associated R47H mutation, and other artificial mutations introduced in the same location, markedly reduced the affinity of TREM2 for ApoE. These findings reveal a link between two Alzheimer disease risk factors and may provide important clues to the pathogenesis of Nasu-Hakola disease and other neurodegenerative disorders.     

DAP12 Stabilizes the C-terminal Fragment of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) and Protects against LPS-induced Pro-inflammatory Response

Triggering receptor expressed on myeloid cells 2 (TREM2) is a DAP12-associated receptor expressed in microglia, macrophages, and other myeloid-derived cells. Previous studies have suggested that TREM2/DAP12 signaling pathway reduces inflammatory responses and promotes phagocytosis of apoptotic neurons. Recently, TREM2 has been identified as a risk gene for Alzheimer disease (AD). Here, we show that DAP12 stabilizes the C-terminal fragment of TREM2 (TREM2-CTF), a substrate for γ-secretase. Co-expression of DAP12 with TREM2 selectively increased the level of TREM2-CTF with little effects on that of full-length TREM2. The interaction between DAP12 and TREM2 is essential for TREM2-CTF stabilization as a mutant form of DAP12 with disrupted interaction with TREM2 failed to exhibit such an effect. Silencing of either Trem2 or Dap12 gene significantly exacerbated pro-inflammatory responses induced by lipopolysaccharides (LPS). Importantly, overexpression of either full-length TREM2 or TREM2-CTF reduced LPS-induced inflammatory responses. Taken together, our results support a role of DAP12 in stabilizing TREM2-CTF, thereby protecting against excessive pro-inflammatory responses.     

Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1)-mediated Bcl-2 Induction Prolongs Macrophage Survival

Triggering receptor expressed on myeloid cells 1 (TREM-1) is a superimmunoglobulin receptor expressed on myeloid cells that plays an important role in the amplification of inflammation. Recent studies suggest a role for TREM-1 in tumor-associated macrophages with relationship to tumor growth and progression. Whether the effects of TREM-1 on inflammation and tumor growth are mediated by an alteration in cell survival signaling is not known. In these studies, we show that TREM-1 knock-out macrophages exhibit an increase in apoptosis of cells in response to lipopolysaccharide (LPS) suggesting a role for TREM-1 in macrophage survival. Specific ligation of TREM-1 with monoclonal TREM-1 (mTREM-1) or overexpression of TREM-1 with adeno-TREM-1 induced B-cell lymphoma-2 (Bcl-2) with depletion of the key executioner caspase-3 prevents the cleavage of poly(ADP-ribose) polymerase. TREM-1 knock-out cells showed lack of induction of Bcl2 with an increase in caspase-3 activation in response to lipopolysaccharide. In addition overexpression of TREM-1 with adeno-TREM-1 led to an increase in mitofusins (MFN1 and MFN2) and knockdown of TREM-1 decreased the expression of mitofusins suggesting that TREM-1 contributes to the maintenance of mitochondrial integrity favoring cell survival. Investigations into potential mechanisms by which TREM-1 alters cell survival showed that TREM-1-induced Bcl-2 in an Egr2-dependent manner. Furthermore, our data shows that expression of Egr2 in response to specific ligation of TREM-1 is ERK mediated. These data for the first time provide novel mechanistic insights into the role of TREM-1 as an anti-apoptotic protein that prolongs macrophage survival.     

The Triggering Receptor Expressed on Myeloid Cells 2: A Molecular Link of Neuroinflammation and Neurodegenerative Diseases

The triggering receptor expressed on myeloid cells (TREM) 2 is a member of the immunoglobulin superfamily of receptors and mediates signaling in immune cells via engagement of its co-receptor DNAX-activating protein of 12 kDa (DAP12). Homozygous mutations in TREM2 or DAP12 cause Nasu-Hakola disease, which is characterized by bone abnormalities and dementia. Recently, a variant of TREM2 has also been associated with an increased risk for Alzheimer disease. The selective expression of TREM2 on immune cells and its association with different forms of dementia indicate a contribution of this receptor in common pathways of neurodegeneration.