趋化因子在HBV感染发病中的作用

乙型肝炎是一种以局部炎性为主的感染性疾病,乙型肝炎病毒（HBV）感染宿主细胞后可诱导宿主细胞中趋化因子分泌及其受体表达,趋化因子／受体的相互作用进一步介导中性粒细胞、淋巴细胞等向炎症部位聚集,参与组织损伤;同时诱导T、B细胞分化成熟,对乙型肝炎的发展与转归、肝组织的损伤与修复有重要影响。HBV引发的慢性乙型肝炎（CHB）以Th1细胞性炎性反应为主,研究表明乙型肝炎中某些趋化因子在肝脏高表达,其受体CXCR3和CCR5在Th1细胞高表达。趋化因子尤其是CXC和CC亚家族趋化因子在趋化Th1细胞中发挥重要的作用：     

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。     

髓系细胞触发受体-1研究进展

髓系细胞表达的触发受体1（triggering receptor expressed on myeloid cells-1,TREM-1）是主要表达于巨噬细胞、中性细胞等的表面受体蛋白,它属于免疫球蛋白超家族的成员,主要由赖氨酸残基的跨膜结构域、V型Ig样胞外结构域和缺乏信号基序的胞浆结构域等三个部分组成。TREM-1分子在感染性疾病中发挥重要作用,通过其和细胞外受体蛋白DAP-12结合,引起下游信号通路活化,导致多种炎症介质的分泌,具有预激和诱导炎症反应的作用,对感染性疾病的诊断起到重要作用。但最近研究显示TREM-1不仅在感染性组织中表达增高,在非感染性炎症、结缔组织及肿瘤组织中也有增高表现,本文就TREM-1最新研究进展做一综述。     

TLR与足细胞损伤

TLRs（Toll—likereceptors）是一类重要的模式识别受体家族,主要调节灭然免疫反应。研究发现在。肾脏固有细胞及间质细胞都有TLR表达,其介导的炎性反应参与了许多肾脏疾病的发生。多种足细胞标志蛋白的发现加快了足细胞表面分子的研究进程。目前已发现足细胞表面有TLR的表达,且TLR的表达与足细胞的损伤有关。     

Th17细胞及其在器官移植排斥反应中的作用

最近发现的辅助T细胞17（T helper cell 17,Th-17）是不同于辅助T细胞1型（Thelpercell1,Th-1）,辅助T细胞2型（Thelpercell2,Th-2）及调节性T细胞（regulatory T cell,Treg）的T细胞亚群,有其独立的分化和发育调节,且互相影响。它由初始T细胞在转化生长因子B（transforming growth factor B,TGF—B）与白细胞介素6（interleukin6,IL-6）、白细胞介素23（interleukin23,1L23）联合作用及转录因子维甲酸相关孤儿素受体γt（retinoic acid related orphan nuclear receptorm,ROR-γt）的协同诱导精细的调节下分化而来。其主要分泌的生物效应分子白细胞介素17（Interleukin17,IL-17）是一种促炎性反应细胞因子,在免疫和造血系统等发挥重要的作用。而器官移植排斥反应的本质就是炎性反应。因此深入研究Th-17细胞分化及其相关生物效应,有助认识其在器官移植排斥中的病理机制,也为治疗移植排斥反应提供新的靶点和途径。     

PARP-1与中枢神经系统疾病的关系

聚腺苷酸二磷酸核糖基聚合酶1[poly（ADP-ribose）pdymerase-1,PARP-1]是-种广泛存在于真核生物细胞核中的蛋白酶,在中枢神经系统的疾病发生中扮演着重要的角色。在外界损伤刺激下,PARP-1易被受损的DNA激活,进而通过不同途径影响神经细胞的生理功能,引起细胞炎性反应,甚至导致细胞死亡,触发中枢神经系统疾病的发生。抑制PARP-1在治疗慢性和急性的中枢神经系统疾病的作用也越来越受到重视。     

TNF-α及其受体在格林巴利综合征中的作用

格林巴利综合征（Guillain-Barrésyndrome,GBS）是一种以周围神经和神经根的脱髓鞘及小血管周围淋巴细胞和巨噬细胞的炎性反应为病理特点的自身免疫性疾病。目前GBS的确切病因还不十分清楚,但是越来越多的研究表明,细胞因子在GBS的发生、发展过程中起到重要的作用,其中TNF-α及其受体在GBS的发病机制中更是扮演着重要的角色。本文就TNF-α及其受体在GBS发病过程中的作用进行综述。     

乳酸受体GPR81的研究进展

GPR81是乳酸的特异性受体,具有调节脂肪细胞发育和分化、抑制脂肪分解、抑制炎性反应,以及调节脑能量代谢、脑血流量和神经元功能的协同变化等生物学功能。GPR81生物学功能的分子机制包括:(1)通过GPR81/Gi/c AMP信号转导通路抑制脂肪分解和调节脑能量代谢、脑血流量和神经元功能的协同变化;(2)通过GPR81/β-arrestin 2/NF-κB及GPR81/β-arrestin 2/NLRP3信号通路抑制巨噬细胞炎性反应。GPR81功能异常与肥胖、血脂异常、胰岛素抵抗、糖耐量减低和2型糖尿病密切相关,还可能参与了颞叶癫痫、中枢性疲乏及缺血性脑血管疾病的发生发展。就乳酸受体GPR81在脂质代谢、炎性反应及中枢神经系统中的作用进行综述。     

高迁移率族蛋白1在脓毒症血管内皮细胞激活过程中的作用

血管内皮细胞激活是脓毒症病理生理过程的中心环节。活化的血管内皮细胞为炎症介质的聚集和迁移提供了重要的场所,是放大炎症反应的前提条件。高迁移率族蛋白1（high-mobility group box protein1,HMGB1）是脓毒症晚期致死性的促炎介质,维持并延长了脓毒症病理过程。HMGBl通过晚期糖基化终产物受体（advanced glycation end products receptor,RAGE）对血管内皮细胞有重要的激活作用。     

高速泳动族蛋白1的致炎症作用机制

高速泳动族蛋白1(high-mobility group box 1,HMGB1)是一种高度保守的DNA结合蛋白,具有维持核小体结构和调节基因转录的功能,近来发现它是炎性反应强有力的促炎因子。在大多炎性疾病,特别是脓毒症病例中,HMGB1的血清和组织水平均显著升高,而且它与其受体如糖基化终末产物受体(receptor for advanced glycation end products,RAGE)、Toll样受体4(toll-like receptor,TLR4)、Toll样受体2(TLR2)等相互作用促进炎性疾病的发展。为了进一步了解HMGB1,本文就HMGB1的结构、生物学活性、与免疫细胞相互作用、细胞表面受体、以及拮抗HMGB1的药物等进行综述。     

TREM-1 deficiency attenuates the inflammatory responses in LPS-induced murine endometritis

Endometritis, which is usually caused by bacterial infection, is characterized by high levels of pro-inflammatory cytokines and a high infertility rate. Triggering receptor expressed on myeloid cells-1 (TREM-1) has been recognized as a potent amplifier of inflammatory reactions. Studies have demonstrated reduced inflammatory responses and mortality rates of animals with bacterial infection due to the blocking of TREM-1 expression. However, whether TREM-1 deficiency could alleviate the inflammatory reaction in bacterial endometritis is still unclear. Here, TREM-1 knock-out (Trem-1^−/−) mice were used to inhibit TREM-1 signalling to evaluate its role in inflammatory reactions after a highly pathogenic LPS infection in mice uteri. The results demonstrated that TREM-1 deficiency attenuated the inflammation in mice uteri; markedly reduced the number of polymorphonuclear neutrophils; and suppressed interleukin-1β (IL-1β), IL-6, and tumour necrosis factor-α (TNF-α) concentrations in serum as well as their production in inflamed uteri after LPS stimulation. Our results illustrate an anticipated pathogenic impact of TREM-1 on endometritis during LPS infection and indicate that blocking of TREM-1 in LPS-induced endometritis holds considerable promise for blunting excessive inflammation.     

Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes

We have identified new activating receptors of the Ig superfamily expressed on human myeloid cells, called TREM (triggering receptor expressed on myeloid cells). TREM-1 is selectively expressed on blood neutrophils and a subset of monocytes and is up-regulated by bacterial LPS. Engagement of TREM-1 triggers secretion of IL-8, monocyte chemotactic protein-1, and TNF-alpha and induces neutrophil degranulation. Intracellularly, TREM-1 induces Ca2+ mobilization and tyrosine phosphorylation of extracellular signal-related kinase 1 (ERK1), ERK2 and phospholipase C-gamma. To mediate activation, TREM-1 associates with the transmembrane adapter molecule DAP12. Thus, TREM-1 mediates activation of neutrophil and monocytes, and may have a predominant role in inflammatory responses.     

Innate immune responses to TREM-1 activation: overlap, divergence, and positive and negative cross-talk with bacterial lipopolysaccharide

TREM-1 (triggering receptor expressed on myeloid cells-1) is an orphan immunoreceptor expressed on monocytes, macrophages, and neutrophils. TREM-1 associates with and signals via the adapter protein DAP12/TYROBP, which contains an ITAM. TREM-1 activation by receptor cross-linking has been shown to be proinflammatory and to amplify some cellular responses to TLR ligands such as bacterial LPS. To investigate the cellular consequences of TREM-1 activation, we have characterized global gene expression changes in human monocytes in response to TREM-1 cross-linking in comparison to and combined with LPS. Both TREM-1 activation and LPS up-regulate chemokines, cytokines, matrix metalloproteases, and PTGS/COX2, consistent with a core inflammatory response. However, other immunomodulatory factors are selectively induced, including SPP1 and CSF1 (i.e., M-CSF) by TREM-1 activation and IL-23 and CSF3 (i.e., G-CSF) by LPS. Additionally, cross-talk between TREM-1 activation and LPS occurs on multiple levels. Although synergy in GM-CSF protein production is reflected in commensurate mRNA abundance, comparable synergy in IL-1beta protein production is not. TREM-1 activation also attenuates the induction of some LPS target genes, including those that encode IL-12 cytokine family subunits. Where tested, positive TREM-1 outputs are greatly reduced by the PI3K inhibitor wortmannin, whereas this attenuation is largely PI3K independent. These experiments provide a detailed analysis of the cellular consequences of TREM-1 activation and highlight the complexity in signal integration between ITAM- and TLR-mediated signaling.     

Functional genomics of silencing TREM-1 on TLR4 signaling in macrophages

Triggering receptor expressed on myeloid cells 1 (TREM-1) is a recently discovered molecule that is expressed on the cell surface of monocytes and neutrophils. Engagement of TREM-1 triggers synthesis of proinflammatory cytokines in response to microbes, but the extent and mechanism by which TREM-1 modulates the inflammatory response is poorly defined. In the present study, we investigated the functional effects of blocking TREM-1 on the Toll-like receptor (TLR)4-mediated signaling pathway in macrophages. By transfecting cells with small hairpin interfering RNA molecules to TREM-1 (shRNA), we confirmed that TREM-1 mRNA and protein expression was greatly attenuated in RAW cells in response to treatment with LPS. PCR array for genes related to or activated by the TLR pathway revealed that although the expression of TLR4 itself was not significantly altered by silencing of TREM-1, expression of several genes, including MyD88, CD14, IkappaBalpha, IL-1beta, MCP-1, and IL-10 was significantly attenuated in the TREM-1 knockdown cells in response to treatment with LPS. These data indicate that expression of TREM-1 modulates the TLR signaling in macrophages by altering the expression of both adaptor and effector proteins that are critical to the endotoxin response.     

Lipopolysaccharide-induced up-regulation of triggering receptor expressed on myeloid cells-1 expression on macrophages is regulated by endogenous prostaglandin E2

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a recently identified cell surface molecule that is expressed by neutrophils and monocytes. TREM-1 expression is modulated by various ligands for TLRs in vitro and in vivo. However, the influence of PGE(2), a potential mediator of inflammation, on TREM-1 expression has not been elucidated. In this study, we examined the effects of PGE(2) on LPS-induced TREM-1 expression by resident murine peritoneal macrophages (RPM) and human PBMC. PGE(2) significantly induced murine TREM-1 (mTREM-1) expression by RPM. Up-regulation of TREM-1 expression was specific to PGE(2) among arachidonic acid metabolites, while ligands for chemoattractant receptor-homologous molecule expressed on Th2 cells and the thomboxane-like prostanoid receptor failed to induce mTREM-1 expression. PGE(2) also increased expression of the soluble form of TREM-1 by PBMC. LPS-induced TREM-1 expression was regulated by endogenous PGE(2) especially in late phase (>2 h after stimulation), because cyclooxygenase-1 and -2 inhibitors abolished this effect at that points. A synthetic EP4 agonist and 8-Br-cAMP also enhanced mTREM-1 expression by RPM. Furthermore, protein kinase A, PI3K, and p38 MAPK inhibitors prevented PGE(2)-induced mTREM-1 expression by RPM. Activation of TREM-1 expressed on PGE(2)-pretreated PBMC by an agonistic TREM-1 mAb significantly enhanced the production of IL-8 and TNF-alpha. These findings indicate that LPS-induced TREM-1 expression on macrophages is mediated, at least partly, by endogenous PGE(2) followed by EP4 and cAMP, protein kinase A, p38 MAPK, and PI3K-mediated signaling. Regulation of TREM-1 and the soluble form of TREM-1 expression by PGE(2) may modulate the inflammatory response to microbial pathogens.     

Inhibition of TREM-1 attenuates inflammation and lipid accumulation in diet-induced nonalcoholic fatty liver disease

In the liver tissues of obese diabetic or nondiabetic patients, triggering receptor expressed on myeloid cells-1 (TREM-1) is usually found to be upregulated, thus leading to upregulation of various inflammatory cytokines and lipid accumulation. On the other hand, nonalcoholic fatty liver disease (NAFLD), characterized by excess lipid accumulation, and inflammatory injury in liver, is becoming an epidemic disease, globally. In the present study, we aimed to investigate the biological role and the underlying mechanisms of TREM-1 in NAFLD. upregulation of TREM-1 occurred in high-fat diet (HFD)-induced mice NAFLD model and oleic acid-treated HepG2 and primary mouse hepatocytes cell model at messenger RNA and protein levels. Functional studies established that overexpression of TREM-1 displayed hyperlipidemia, and increased in inflammatory indicators and lipid accumulation-related genes, which was ameliorated by knockdown of TREM-1. Our results also showed that obvious lipid accumulation and inflammatory injury occurred in the liver tissue of HFD-fed mice, while treatment with lentiviral vector short hairpin TREM showed marked improvement in tissue morphology and architecture and less lipid accumulation, thus deciphering the mechanism through which knockdown of TREM-1 ameliorated the inflammatory response and lipid accumulation of NAFLD mice through inactivation of the nuclear factor-κB (NF-κB) and PI3K/AKT signal pathways, respectively. In conclusion, TREM-1/NF-κB and TREM-1/PI3K/AKT axis could be an important mechanism in ameliorating the inflammatory response and lipid accumulation, respectively, thus shedding light on the development of novel therapeutics to the treatment of NAFLD.     

Blocking TREM-1 signaling prolongs survival of mice with Pseudomonas aeruginosa induced sepsis

TREM-1 is a recently discovered receptor expressed on neutrophils and macrophages. Blocking of TREM-1 signaling improves the survival of mice with bacterial sepsis. However, the precise mechanism by which TREM-1 modulates the inflammatory responses is poorly defined. In this study, we investigated the role of TREM-1 in Pseudomonas aeruginosa-induced peritonitis. Our results showed that TREM-1 was not expressed on lymphocytes but emerged on the cell surface of neutrophils and peritoneal macrophages. Blockade of TREM-1 signaling significantly prolonged survival of mice with P. aeruginosa-induced peritonitis. However, blocking TREM-1 signaling had no effect on macrophage phagocytosis in vitro. Interestingly, the expression of the costimulatory molecules CD40 and CD86 on macrophages was significantly decreased after blocking TREM-1 signaling. Furthermore, interfering with TREM-1 engagement led to significant reduction of pro-inflammatory mediators such as IL-1, TNF-α, MCP-1 and IFN-γ. Therefore, our results showed that TREM-1 could be a potential therapeutic target for bacterial sepsis.     

Triggering receptor expressed on myeloid cells-1 in neutrophil inflammatory responses: differential regulation of activation and survival

Polymorphonuclear neutrophils (PMN) are crucial in the innate host defense by their ability to rapidly accumulate in inflamed tissues and clear a site of infection from microbial pathogens by their potent effector mechanisms. The triggering receptor expressed on myeloid cells (TREM)-1 is a recently described activating receptor on PMN with an important role in inflammation. However, the effects of TREM-1 stimulation on a cellular level remain to be further defined. To characterize TREM-1-mediated activation of human PMN, we evaluated the effect of receptor ligation on PMN effector functions. Activation via TREM-1 induces immediate degranulation of neutrophilic granules resulting in the release of IL-8, respiratory burst, and phagocytosis. TREM-1 ligation synergizes with the activation by the Toll-like receptors (TLR) ligands LPS, Pam(3)Cys, and R-848. In contrast, no synergy between TREM-1- and TLR-mediated stimulation was observed concerning PMN survival, whereas TLR-mediated stimuli protect PMN from apoptosis, concurrent TREM-1 activation neutralizes these anti-apoptotic effects. These results give a new perspective for the regulation of neutrophil inflammatory responses emphasizing the importance of TREM-1 in innate immunity.