髓样细胞表达的触发受体-1研究进展

髓样细胞表达的触发受体-1（TREM-1）具有激发和放大炎症反应的作用,最初发现于脓毒血症,一直以来被看作是诊断感染性疾病的标志物。但最近研究显示TREM-1在感染及非感染性炎症中表达均增高,而且认为TREM-1的阻断可成为治疗急、慢性炎症性疾病的一种新的方法。因而对TREM-1的结构功能、表达情况、信号转导机制、可溶性形式及与全身性炎症反应的关系和以其为靶点的治疗作用等进行研究有重大意义。     

髓样细胞表达的触发受体-1与炎症信号转导的研究进展

研究表明髓样细胞表达的触发受体-1(TREM-1)参与了炎性反应的级联放大过程.细菌的某些成分可以上调细胞表面TREM-1的表达,并且能和TREM-1配体协同激活TREM-1受体向下游传递信号.TREM-1被激活后会诱导前炎性因子的产生并引起相关的炎症反应.由于TREM-1是明显放大内毒素脂多糖(LPS)所引起的炎性反应的关键介质,因此对于TREM-1激活炎症信号通路的研究取得了一定的进展.然而,TREM-1在协同Toll样受体激活炎性反应的信号通路的具体机制尚未完全明晰.专注于TREM-1的信号转导,阐明与此通路相关的信号分子,如TLR、DAP-12、MAPKs、NTAL、CARD9、NLRs的作用,为进一步揭示脓毒症的发病机制并寻找新的治疗靶点.     

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调.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.     

抑制髓样细胞触发受体-1(TREM-1)减轻慢性间歇性低氧诱发的模型小鼠动脉粥样硬化

目的 探究髓样细胞触发受体-1(TREM-1)在慢性间歇性低氧(CIH)诱发的动脉粥样硬化(AS)中作用。方法 将ApoE^-/-小鼠随机分为空白组、模型组和实验组。模型组和实验组小鼠饲养于低氧环境,给予高脂饲料喂养;实验组小鼠高脂饲养4周后,腹腔注射TREM-1抑制剂LR12(5 mg/kg),连续干预8周。饲养12周后,检测血清总胆固醇(TC)、低密度脂蛋白(LDL)、三酰甘油(TG)、肿瘤坏死因子α(TNF-α)、白细胞介素1(IL-1β)、白细胞介素10(IL-10)水平;组织学分析主动脉TREM-1表达、斑块面积及巨噬细胞水平。结果 与空白组相比,模型组小鼠主动脉TREM-1表达量显著升高(P<0.05)。相比于模型组,实验组小鼠主动脉斑块显著减少,血清血脂(TC、LDL、TG)及炎性因子(TNF-α、IL-1β、IL-10)水平显著降低,主动脉斑块及斑块浸润巨噬细胞、TREM-1表达显著减少(P<0.05),且斑块中TREM-1表达与巨噬细胞为共定位。结论 TREM-1参与CIH诱发的AS发生发展,抑制TREM-1能够减轻CIH诱发的AS,其...     

VIP对LPS应激的小鼠成纤维细胞TREM-2表达的影响及其机制

目的　观察血管活性肠肽（vasoactive intestinal peptide,VIP）对脂多糖（lipopolysaccharides, LPS）应激的小鼠成纤维细胞髓样细胞表达触发受体-2（TREM-2）表达的影响,并初步探讨其信号转导通路。 方法　利用LPS腹腔注射建立急性肺损伤（ALI）小鼠模型;采用VIP慢病毒气管滴注,qPCR检测肺组织TREM-2的表达。选用qPCR和流式细胞术检测VIP对LPS应激的小鼠成纤维细胞TREM- 2表达的影响;并观察PKC信号通路阻断剂（H-7）、PKA信号通路阻断剂（H- 89）、MAPK信号通路阻断剂（PD98059）和CaM信号通路阻断剂（W-7）对VIP调控TREM- 2表达的影响。 结果　ALI时小鼠肺组织TREM-2 mRNA表达降低,而VIP可上调肺组织TREM- 2 mRNA的表达。LPS下调小鼠成纤维细胞TREM- 2 mRNA的表达,VIP可呈时间依赖性上调TREM- 2 mRNA的表达（0、3 、6 、12和24 h）,且在6 h达到峰值;并呈剂量相关性上调TREM- 2 mRNA的表达（10-10、10-9、10-8和10-7 mol/L）,以10-8 mol/L作用最明显。VIP对LPS应激6 h增加小鼠成纤维细胞TREM-2 mRNA和蛋白表达的效应可被H-7、PD98059以及W- 7所阻断。 结论　LPS下调小鼠成纤维细胞TREM-2的表达,而VIP可上调LPS应激的小鼠成纤维细胞TREM- 2 mRNA的表达,其胞内信号转导途径可能与PKC、MAPK及CaM有关。     

血管活性肠肽对RAW264.7小鼠巨噬细胞TREM-1功能的影响

目的　观察血管活性肠肽(VIP)对RAW264.7小鼠巨噬细胞髓样细胞表达的触发受体-1（TREM-1）功能的影响。 方法　以小鼠巨噬细胞系RAW264.7为研究对象,细胞接种于培养板后采用TREM-1的单克隆激动抗体激活TREM-1,VIP预处理组采用10 nM的VIP进行干预。1 h后采用Western blot法检测胞内PLC-γ磷酸化改变,采用DCFH-DA荧光探针检测胞内活性氧簇（ROS）的含量;6 h后,采用real-time PCR法检测巨噬细胞TREM-1受体激活后下游靶基因肿瘤坏死因子-α（TNF-α）和单核细胞趋化蛋白-1（MCP-1）的基因表达;12 h后,采用ELISA法检测细胞培养上清液TNF-α和MCP-1的蛋白含量。 结果　采用TREM-1单克隆激动抗体处理小鼠巨噬细胞后,可显著增高胞内PLC-γ磷酸化水平、ROS含量,以及TNF-α和MCP-1的mRNA与蛋白水平,而VIP预处理可明显抑制单克隆激动抗体所诱导的上述反应。 结论　VIP可抑制RAW264.7小鼠巨噬细胞TREM-1激活后诱导的功能改变,从而发挥抗氧化抗炎的作用。     

髓系细胞触发受体-1与动脉粥样硬化关系的研究进展

髓系细胞触发受体-1(TREM-1)是新近发现的免疫球蛋白超家族活化跨膜受体,能够触发和扩大炎症反应,在动脉粥样硬化(AS)的炎症机制中起重要作用。本文从TREM-1的结构特点、表达方式、配体结合、信号通路等论述其与AS发生发展及动脉斑块稳定性的关系和作用,为临床研究AS的靶向治疗提供参考和借鉴。     

血清可溶性髓样细胞触发受体1对活动性肺结核的早期预警和预后判断价值

目的检测活动性肺结核(ATB)患者血清可溶性髓样细胞触发受体1(s TREM-1)含量并分析其临床意义。方法收集东莞市慢性病防治院确诊的ATB患者78例和健康志愿者40例,全自动血球分析仪检测外周血中性粒细胞和单核细胞绝对值,ELISA检测血清s TREM-1含量,Pearson相关分析其相关性。结果 ATB患者外周血中性粒细胞绝对值,单核细胞绝对值和血清s TREM-1含量均显著增高,且痰涂片结核分枝杆菌(MTB)阳性患者显著高于痰涂片MTB阴性患者,常规抗结核药物治疗前显著高于治疗后。以528.14 pg/m L为血清s TREM-1含量检测截断点时,痰涂片MTB阳性的结核确诊率为100%。Pearson相关性分析显示ATB患者外周血中性粒细胞和单核细胞绝对值均与患者血清s TREM-1含量呈正相关。结论 s TREM-1对ATB的早期预警及预后有重要参考价值。     

类风湿关节炎患者血清可溶性髓样细胞触发受体-1、白介素-17水平分析

目的检测类风湿关节炎血清可溶性髓样细胞触发受体1(soluble triggering receptors expressed on myeloid cells-1,sTREM-1)与白介素-17(interleukin-17,IL-17)的血清水平,探讨两者在类风湿关节炎(rheumatoid arthritis,RA)中的变化,分析两者在发病过程中可能作用及临床应用前景。方法应用双抗体夹心酶联免疫吸附试验(ELISA)检测114例RA患者(稳定期组46例、活动期组68例),39例其他风湿免疫系统疾病患者(非RA组)及32例正常对照者血清中可溶性髓样细胞触发受体1(sTREM-1)与白介素-17(IL-17)的水平,同时检测类风湿因子(RHF)、C反应蛋白(CRP)、抗环瓜氨酸肽抗体(anti-CCP)及血沉(ESR)。结果RA组sTREM-1、IL-17较正常对照组高(P=0.03,0.02),且sTREM-1在活动期RA明显高于稳定期RA(P=0.02);RA组血清中sTREM-1与IL-17(r=0.97,P=0.001)、CRP(r=0.255,P=0.006)及ESR(r=0.442,P=0.001)变化呈正相关;未发现sTREM-1、IL-17血清水平变化与病程相关(P=0.64,0.50);两项血清学指标在RA组及非RA组间无统计学意义(P=0.39,0.09)。结论 RA患者sTREM-1水平与反应疾病活动的指标如CRP、ESR水平之间具有良好的相关性;sTREM-1参与RA的发病及疾病活动过程,有可能成为类风湿性关节炎活动性新指标;血清sTREM-1与IL-17水平变化呈正相关,两者在RA发病及病情活动中可能起协同作用。     

髓样细胞表达的激发型受体家族的研究进展

髓样细胞表达的激发型受体(TREM)是新近发现的免疫球蛋白超家族的一个受体家族,它主要包括TREM-1、TREM-2、TLT-1和TLT-2四个家族成员.自2000年发现TREM-1以来,TREM家族就成为了人们关注的对象,特别是近年来针对TREM-1与炎症反应的关系及TLT-2配体的研究更是成为了研究的热点.因此对TREM家族全面的认识,有助于其家族信号通路和生物学功能的进一步研究.     

Expression and function of triggering receptor expressed on myeloid cells-1 (TREM-1) on canine neutrophils

The dog is both a valued veterinary species and a widely used translational model for sepsis research. However, relatively little work has been performed evaluating potential biomarkers present during canine infection. Triggering receptor expressed on myeloid cells-1 (TREM-1) has shown promise as a biomarker for infection and pneumonia in humans. Here we describe, for the first time, the expression and function of the canine orthologue of TREM-1. Expression of TREM-1 on canine neutrophils is significantly up-regulated by stimulation with microbial agonists of TLR2/6, TLR1/2, and TLR4/MD2. Kinetics of TREM-1 protein up-regulation are rapid, with significant increases observed within 2 hr of neutrophil activation. Functionally, canine TREM-1 synergistically enhances LPS-induced production of IL-8, TNF-α and a canine orthologue of CXCL1. Collectively, these data suggest that TREM-1 expression in dogs, as it is in humans, is an amplifier of pro-inflammatory responses to microbial products. These results have direct application to veterinary diagnostics as well as the potential to enhance the utility of canine disease models in the assessment of potential therapeutics in the treatment of human sepsis.     

Triggering receptor expressed on myeloid cells in the pathogenesis of periodontitis: potential novel treatment strategies

Introduction: Periodontal diseases are polymicrobial inflammatory disorders of the tissue, ligament, and bone structures supporting teeth. Periodontitis (inflammation with corresponding loss of attachment) affects 40–50% of adults. Recently, members of the Triggering Receptor on Myeloid Cell (TREM) family have been studied to determine their relationship to these diseases.

Areas covered: TREM-1 is a receptor expressed on the surface of PMNs, monocytes, macrophages, dendritic cells, vascular smooth muscle cells, and keratinocytes upregulated in the presence of periodontal inflammation. TREM-1 expression can be upregulated by oral bacterium Porphyromonas gingivalis that can be abrogated by a sub-antimicrobial dose of doxycycline. When cleaved from the cell surface, a soluble form of TREM-1 (sTREM-1) can be used as a biomarker of inflammation and might also provide a link between oral and systemic inflammation. While less understood, TREM-2 has a role in osteoclastogenesis which could contribute to the alveolar bone destruction seen in more advanced periodontitis.

Expert commentary: Additional studies to simulate biofilm microenvironment in TREM research are warranted. Longitudinal studies determining TREM-1, sTREM-1, and TREM-2 levels in tissues over time and progression of periodontal diseases would provide valuable information in the role of TREM receptors as indicators of or contributors to the disease process.     

Blockade of Triggering receptor expressed on myeloid cells-1 as a new therapy of arthritis

Triggering receptor expressed on myeloid cells (TREM)-1 belongs to an immunoglobulin super family and is expressed on neutrophils, mature monocytes and macrophages. The engagement of TREM-1 synergizes with several Toll Like Receptors (TLR) activation in amplifying the inflammatory response. TREM-1 blockade using a fusion protein containing murine TREM-1 extracellular domain and human immunoglobulin Fc portion was reported to prevent death in mouse models of microbial peritonitis and protect from organ damage during other inflammatory diseases. There are many reports suggesting the involvement of TREM-1 in the pathogenesis of rheumatoid arthritis. Blockade of TREM-1 could be a new therapeutic target in rheumatoid arthritis without impairing the host defense against microbes. In this report, we outline the role of TREM-1 and the trial of developing anti-rheumatic drugs by targeting its ligand.     

Regulation of triggering receptor expressed on myeloid cells 1 expression on mouse inflammatory monocytes

Triggering receptor expressed on myeloid cells 1 (TREM-1) is an activating receptor involved in inflammatory diseases and septic shock. The TREM-1 ligand(s) (TREM-1L) have not yet been identified. In this study, we performed a detailed analysis of the expression of mouse TREM-1 and its ligand(s). Our results demonstrate that TREM-1 is expressed on bone-marrow-derived dendritic cells (BMDC). On bone-marrow-derived macrophages (BMM) its expression is induced in vitro after stimulation by granulocyte–macrophage colony-stimulating factor, interleukin-3 or by myeloid differentiation primary response gene 88 (MyD88)-dependent Toll-like receptor (TLR) ligands. Under steady-state conditions mouse TREM-1 is detectable on a Gr-1⁻ F4/80⁺ monocyte subpopulation bearing markers of resident monocytes, but not on Gr-1⁺ F4/80⁺ inflammatory monocytes. During lipopolysaccharide (LPS)-induced endotoxaemia TREM-1 was also up-regulated on inflammatory Gr-1⁺ F4/80⁺ cells in vivo. In tumour-bearing mice, TREM-1 was up-regulated on Gr-1⁺ F4/80⁺ monocytes, which phenotypically and functionally resembled mononuclear myeloid-derived suppressor cells. Using a soluble TREM-1 fusion protein, we demonstrate that after intravenous injection of LPS TREM-1L was induced on Gr-1⁺ granulocytes and monocytes but not on other cell populations in peripheral blood. This up-regulation on granulocytes was directly mediated by TLR ligands and required the adapter protein MyD88. In contrast to human, mouse platelets expressed TREM-1L neither under steady-state conditions nor after LPS injection in vivo. Our study reveals differential regulation of TREM-1 expression on mouse monocyte subpopulations and improves our understanding of the biological role of TREM-1 during disease.     

The characteristics and pivotal roles of triggering receptor expressed on myeloid cells-1 in autoimmune diseases

Triggering receptor expressed on myeloid cells-1 (TREM-1) engagement can directly trigger inflammation or amplify an inflammatory response by synergizing with TLRs or NLRs. Autoimmune diseases are a family of chronic systemic inflammatory disorders. The pivotal role of TREM-1 in inflammation makes it important to explore its immunological effects in autoimmune diseases. In this review, we summarize the structural and functional characteristics of TREM-1. Particularly, we discuss recent findings on TREM-1 pathway regulation in various autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), type 1 diabetes (T1D), and psoriasis. This receptor may potentially be manipulated to alter the inflammatory response to chronic inflammation and possible therapies are explored in this review.