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.     

先天免疫的研究进展

近来,关于先天免疫的研究有了突飞猛进的进展.特别是在关于模式识别受体的发现和功能研究方面.模式识别受体能识别病原相关的分子模式.先天免疫不但提供抗感染的第一防线而且调控后天获得性免疫的激活.如果没有先天免疫,后天获得性免疫的功能会变得很微弱.Toll样受体是先天免疫的关键感受器和研究最多的模式识别受体.激活的Toll样受体信号传导通路可以很快引起与炎性反应和免疫反应相关的各种基因的表达.所有这些关于研究Toll样受体及其信号通路的新见解已经开始改变我们对炎性反应和免疫反应相关疾病的预防和治疗.     

先天免疫的研究进展

近来,关于先天免疫的研究有了突飞猛进的进展.特别是在关于模式识别受体的发现和功能研究方面.模式识别受体能识别病原相关的分子模式.先天免疫不但提供抗感染的第一防线而且调控后天获得性免疫的激活.如果没有先天免疫,后天获得性免疫的功能会变得很微弱.Toll样受体是先天免疫的关键感受器和研究最多的模式识别受体.激活的Toll样受体信号传导通路可以很快引起与炎性反应和免疫反应相关的各种基因的表达.所有这些关于研究Toll样受体及其信号通路的新见解已经开始改变我们对炎性反应和免疫反应相关疾病的预防和治疗.     

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.     

先天免疫的研究进展

近来,关于先天免疫的研究有了突飞猛进的进展。特别是在关于模式识别受体的发现和功能研究方面。模式识别受体能识别病原相关的分子模式。先天免疫不但提供抗感染的第一防线而且调控后天获得性免疫的激活。如果没有先天免疫,后天获得性免疫的功能会变得很微弱。Toll样受体是先天免疫的关键感受器和研究最多的模式识别受体。激活的Toll样受体信号传导通路可以很快引起与炎性反应和免疫反应相关的各种基因的表达。所有这些关于研究Toll样受体及其信号通路的新见解已经开始改变我们对炎性反应和免疫反应相关疾病的预防和治疗。     

髓样细胞触发受体与溃疡性结肠炎及其相关癌变的研究进展北大核心CSCD

越来越多研究表明炎症在恶性肿瘤发生发展中有举足轻重的作用。在很大程度上与免疫细胞参与恶性肿瘤有关,其中关键是模式识别受体(PRRs)激活的免疫应答。髓样细胞触发受体(TREMs)作为PRRs的一员,来自于髓样细胞,主要成员为TREM-1和TREM-2。已有研究表明,TREMs广泛参与多种炎症以及恶性肿瘤的生长过程,包括结肠癌。本文主要讨论溃疡性结肠炎及其相关癌变机制以及TREMs在炎症相关结肠癌中的研究进展。     

髓样细胞表达的激发受体的研究进展

髓样细胞表达的激发受体(TREM),是主要表达在单核/巨噬细胞、中性粒细胞、树突状细胞、破骨细胞上的含有激活受体和抑制受体的受体家族。人类TREM的激活受体至少包括:TREM-1、TREM-2。在小鼠体内除发现Trem-1、Trem-2外,还有Trem-3。TREM-1和Trem-3与加强炎症反应有关,参与炎症性疾病的发生和发展;TREM-2影响树突状细胞和破骨细胞等细胞的成熟;而至今被证实的抑制受体只有TLT-1,它通过胞内段的ITIM介导抑制作用,调节激活受体的功能。     

炎症性疾病早期诊断的新指——sTREM-1

髓系细胞表达的触发受体-1(TREM-1)是新近确认的一个与炎症相关的免疫球蛋白超家族成员,表达于中性粒细胞、成熟的单核细胞、巨噬细胞表面.多种细菌性成分能使细胞表面的TREM-1表达增加,后者与Toll样受体协同作用,激发炎症因子的产生.最新的研究发现,感染过程中一种可溶性TREM-1(sTREM-1)可释放进入体液,并且与多种疾病如肺炎、细菌性脑膜炎、炎症性肠病密切相关,成为一种早期诊断炎症性疾病的新指标.     

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。     

先天免疫Toll样受体在哮喘病中作用的研究进展

哮喘病的高发性和普遍性使哮喘病成为人们极度关注的健康问题,哮喘病的特征是呼吸道阻塞和支气管的过度炎性反应.虽然对后大获得性免疫在哮喘病中的作用已进行了广泛地研究,但是先天免疫在哮喘病中的重要件是最近才被发现的.先大免疫不但提供抗感染的第一道防线,而且调控后天获得件免疫的激活.Toll样受体是先大免疫的关键感受器,它也是研究最多的模式识别受体.激活的Toll样受体信号传导通路可以很快引起与炎性反应和免疫反应相关的各种基因的表达.本义综述了了目前天于Toll样受体在哮喘病中作用的研究进展.     

炎症性疾病早期诊断的新指标—sTREM-1

髓系细胞表达的触发受体-1（TREM-1）是新近确认的一个与炎症相关的免疫球蛋白超家族成员，表达于中性粒细胞、成熟的单核细胞、巨噬细胞表面。多种细菌性成分能使细胞表面的TREM-1表达增加，后者与Toll样受体协同作用，激发炎症因子的产生。最新的研究发现，感染过程中一种可溶性TREM-1（sTREM-1）可释放进入体液，并且与多种疾病如肺炎、细菌性脑膜炎、炎症性肠病密切相关，成为一种早期诊断炎症性疾病的新指标。     

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。     

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.     

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.     

Effects of TREM-1 activation in human neutrophils: activation of signaling pathways, recruitment into lipid rafts and association with TLR4

Neutrophilic polymorphonuclears (PMNs) play an important role in the progression of sepsis-related inflammation and become highly activated by a wide array of ligands on the site. The triggering receptor expressed on myeloid cells-1 (TREM-1) is a recently described receptor that has many effects on human PMN. The engagement of TREM-1 on PMN can induce phagocytosis, reactive oxygen species production and release of myeloperoxidase and IL-8. LPS has a priming effect on these functions. We show in this paper that Lyn, AKT, extracellular signal-regulated kinase 1/2 and Jak2 signaling pathways are elicited following TREM-1 engagement and activation by a monoclonal agonist antibody (anti-TREM-1) in human PMN, leading to the phosphorylation of STAT5 and RelA, a subunit of the nuclear factor-kappa B family. We also show that TREM-1 is recruited to ganglioside M1-lipid rafts in PMN upon stimulation with LPS or anti-TREM-1. Moreover, we observed that Toll-like receptor 4 and TREM-1 co-localize upon stimulation and TREM-1 engagement resulted in the phosphorylation of IL-1R-associated kinase 1, but not its stimulant-induced degradation. These data shed a new light on how various receptors implicated in the innate immune response could interact to insure an efficient inflammatory response upon pathogens-associated aggression.     

Regulation of TREM expression in hepatic macrophages and endothelial cells during acute endotoxemia

Triggering receptor expressed on myeloid cells (TREM) regulates inflammatory responses to lipopolysaccharide (LPS). In these studies, we analyzed the expression of TREM in hepatic macrophages and endothelial cells which play a central role in LPS clearance. LPS administration to C3H/HeOuJ mice resulted in a rapid induction of TREM-1 and TREM-3, but a decrease in TREM-2 in liver macrophages and endothelial cells. The observation that TREM family members are detectable in endothelial cells is novel and demonstrates that their expression is not limited to myeloid cells. LPS-induced alterations in TREM expression were not evident in cells from C3H/HeJ TLR-4 mutant mice, indicating that the response is dependent on TLR-4. IL-1beta and TNFalpha upregulated TREM-1 and TREM-3 expression and suppressed TREM-2 expression in macrophages and endothelial cells. This activity involved PI3-kinase and p38 MAP kinase signaling. Interestingly, no significant differences were noted in TREM expression between wild-type and TNFR1-/- mice treated with LPS. Treatment of macrophages and endothelial cells with LPS upregulated expression of nitric oxide synthase-2 (NOS-2). This was blocked by TREM-1 Fc/fusion protein, indicating that TREM-1 mediates LPS-induced NOS-2 expression. These results suggest that TREM proteins are important in the inflammatory response of hepatic macrophages and endothelial cells to acute endotoxemia.     

Production of soluble triggering receptor expressed on myeloid cells by lipopolysaccharide-stimulated human neutrophils involves de novo protein synthesis

The triggering receptor expressed on myeloid cells (TREM-1) is a recently identified receptor expressed on neutrophils and monocytes. Activation of the receptor induces neutrophils to release the enzyme myeloperoxidase and inflammatory cytokines such as interleukin-8. TREM-1 has an alternatively spliced variant that lacks the transmembrane region, resulting in the receptor being secreted in a soluble form (sTREM-1). Soluble TREM-1 has been detected in plasma during experimental and clinical sepsis and has been advocated as a diagnostic marker of infection for pneumonia and as a prognostic marker for patients with septic shock. We studied TREM-1 surface expression, using flow cytometry, and simultaneously measured sTREM-1 concentrations in culture supernatants of lipopolysaccharide (LPS)-stimulated neutrophils. TREM-1 surface expression was constitutive and was not upregulated upon LPS stimulation. However, sTREM-1 release from neutrophils was significantly upregulated by LPS stimulation (P < 0.0001), an effect that was abrogated by cycloheximide. Soluble TREM-1 is therefore secreted by human neutrophils in response to LPS challenge in a process involving de novo protein synthesis that is not accompanied by an upregulation of the TREM-1 receptor on the surfaces of the cells.