趋化因子及其受体介导的细胞迁移与移植物抗宿主病

移植物抗宿主病(graft-versus-hostdisease,GVHD)是同种异基因骨髓移植中的重要并发征。供者T细胞在输注入受者体内后迁移进入淋巴组织,识别受者同种异基因抗原,被受者抗原递呈细胞(antigenpresentingcell,APC)激活,进而活化、增殖分化,介导急性GVHD的发生。现有的研究已表明,活化的异体效应性T细胞经淋巴组织迁移进入黏膜组织以及实质性靶器官,如消化道、肝脏、肺脏和皮肤,进而造成这些器官和组织的损伤。因此,分子间相互作用尤其是趋化因子及其受体介导的效应性细胞的迁移是GVHD发生发展过程中关键的一环,受到了广泛的关注。进一步以趋化因子及其受体为靶标,亦可能形成有效的免疫生物学治疗,具有广阔的应用前景。     

间充质干细胞表达趋化因子及受体的相关生物学功能

间充质干细胞(mesenchymal stem cells,MSCs)是一群存在于骨髓间质和其他组织间质的干细胞,表达CD34和CD133.近来研究发现,存在于骨髓的间充质干细胞除了能支持造血,向骨细胞、软骨细胞和脂肪细胞进行多向分化外,其分泌的趋化因子及其相关受体在MSCs的信号转导、维持内环境的稳定、损伤修复、免疫调节、支持造血等功能中也发挥了关键性的作用.     

Dual Targeting of the Chemokine Receptors CXCR4 and ACKR3 with Novel Engineered Chemokines

The chemokine CXCL12 and its G protein-coupled receptors CXCR4 and ACKR3 are implicated in cancer and inflammatory and autoimmune disorders and are targets of numerous antagonist discovery efforts. Here, we describe a series of novel, high affinity CXCL12-based modulators of CXCR4 and ACKR3 generated by selection of N-terminal CXCL12 phage libraries on live cells expressing the receptors. Twelve of 13 characterized CXCL12 variants are full CXCR4 antagonists, and four have K_d values <5 nm. The new variants also showed high affinity for ACKR3. The variant with the highest affinity for CXCR4, LGGG-CXCL12, showed efficacy in a murine model for multiple sclerosis, demonstrating translational potential. Molecular modeling was used to elucidate the structural basis of binding and antagonism of selected variants and to guide future designs. Together, this work represents an important step toward the development of therapeutics targeting CXCR4 and ACKR3.     

趋化因子及其受体在连接天然免疫与获得性免疫中的作用

病原侵入组织引起天然免疫中巨噬细胞(Mφ)分泌趋化因子,趋化因子／趋化因子受体的表达与非成熟树突状细胞(DC)的迁移、成熟、归巢以及获得性免疫应答密切相关。整个过程涉及许多趋化因子和趋化因子受体的表达变化,正是这种表达变化的精细调节启动了免疫细胞的定向迁移、归巢和游走,搭起天然免疫和获得性免疫的桥梁。本文综述了趋化因子和趋化因子受体在连接天然免疫和获得性免疫应答中的重要作用。     

趋化因子受体在炎症诱导痛觉中的作用

趋化因子受体最早是在研究白细胞迁移过程中发现的,它在大鼠和小鼠的背根神经节外周感觉神经细胞上也有表达.在炎症情况下,激活的趋化因子受体可以诱导神经细胞上一类重要的镇痛受体—μ-鸦片受体的异源性脱敏,抑制其功能;同时,激活的趋化因子受体还可以增强一类对于痛觉感受非常关键的受体——辣椒素受体的敏感性,使其敏化.趋化因子受体诱导的这2种效应可以通过Gi蛋白信号传导通路增强生物体对痛觉的敏感度.这些结果提示,趋化因子受体可能是免疫系统和神经系统之间交叉调节的桥梁.     

Atorvastatin Upregulates the Expression of miR-126 in Apolipoprotein E-knockout Mice with Carotid Atherosclerotic Plaque

Carotid atherosclerosis (AS) is a chronic inflammatory disease of the carotid arterial wall, which is very important in terms of the occurrence of cerebral vascular accidents. Studies have demonstrated that microRNAs (miRNAs) and their target genes are involved in the formation of atherosclerosis and that atorvastatin might reduce atherosclerotic plaques by regulating the expression of miRNAs. However, the related mechanism is not yet known. In this study, we first investigated the effects of atorvastatin on miR-126 and its target gene, i.e., vascular cell adhesion molecule-1 (VCAM-1) in apolipoprotein E-knockout (ApoE?/?) mice with carotid atherosclerotic plaque in vivo. We compared the expressions of miR-126 and VCAM-1 between the control, atherosclerotic model and atorvastatin treatment groups of ApoE?/? mice using RT-PCR and Western blot. We found the miR-126 expression was significantly down-regulated, and the VCAM-1 expression was significantly up-regulated in the atherosclerotic model group, which accelerated the progression of atherosclerosis in the ApoE?/? mice. These results following atorvastatin treatment indicated that miR-126 expression was significantly up-regulated, VCAM-1 expression was significantly down-regulated and atherosclerotic lesions were reduced. The present results might explain the mechanism by which miR-126 is involved in the formation of atherosclerosis in vivo. Our study first indicated that atorvastatin might exert its anti-inflammatory effects in atherosclerosis by regulating the expressions of miR-126 and VCAM-1 in vivo.     

The Role of Serum Amyloid A1, Adhesion Molecules,Chemokines, and Chemokine Receptors Genes in Chronic Obstructive Pulmonary Disease

Russian Journal of Genetics - Chronic obstructive pulmonary disease (COPD) is a multifactorial chronic inflammatory disease of the respiratory system. A key phenomenon of COPD pathogenesis is...     

趋化因子及趋化因子受体在急性胰腺炎中的研究进展

普遍认为,急性胰腺炎起始于腺泡细胞内的胰蛋白酶原激活,随后引起的炎症反应加剧病情,也是多器官功能衰竭的主要原因。然而,最新的研究表明,急性胰腺炎引起的炎症反应是不依赖于胰蛋白酶原激活的独立病理过程。趋化因子作为能引起细胞趋化的细胞因子,通过与趋化因子受体作用,不但能调控淋巴细胞的生长、成熟和迁移,也参与多种炎症疾病与癌症的病理过程。近年来,多项研究已经阐述趋化因子及趋化因子受体在急性胰腺炎的发病发展过程中起到至关重要的作用。本文总结了CC,CXC和CX3C趋化因子家族成员在参与急性胰腺炎的炎症反应及对胰腺损伤的修复的研究进展,这将为AP临床治疗方案的设计提供新思路。     

Biased Agonism as a Mechanism for Differential Signaling by Chemokine Receptors

Chemokines display considerable promiscuity with multiple ligands and receptors shared in common, a phenomenon that is thought to underlie their biochemical “redundancy.” Their receptors are part of a larger seven-transmembrane receptor superfamily, commonly referred to as G protein-coupled receptors, which have been demonstrated to be able to signal with different efficacies to their multiple downstream signaling pathways, a phenomenon referred to as biased agonism. Biased agonism has been primarily reported as a phenomenon of synthetic ligands, and the biologic prevalence and importance of such signaling are unclear. Here, to assess the presence of biased agonism that may underlie differential signaling by chemokines targeting the same receptor, we performed a detailed pharmacologic analysis of a set of chemokine receptors with multiple endogenous ligands using assays for G protein signaling, β-arrestin recruitment, and receptor internalization. We found that chemokines targeting the same receptor can display marked differences in their efficacies for G protein- or β-arrestin-mediated signaling or receptor internalization. This ligand bias correlates with changes in leukocyte migration, consistent with different mechanisms underlying the signaling downstream of these receptors induced by their ligands. These findings demonstrate that biased agonism is a common and likely evolutionarily conserved biological mechanism for generating qualitatively distinct patterns of signaling via the same receptor in response to different endogenous ligands.     

Myxomavirus Anti-Inflammatory Chemokine Binding Protein Reduces the Increased Plaque Growth Induced by Chronic Porphyromonas gingivalis Oral Infection after Balloon Angioplasty Aortic Injury in Mice

Thrombotic occlusion of inflammatory plaque in coronary arteries causes myocardial infarction. Treatment with emergent balloon angioplasty (BA) and stent implant improves survival, but restenosis (regrowth) can occur. Periodontal bacteremia is closely associated with inflammation and native arterial atherosclerosis, with potential to increase restenosis. Two virus-derived anti-inflammatory proteins, M-T7 and Serp-1, reduce inflammation and plaque growth after BA and transplant in animal models through separate pathways. M-T7 is a broad spectrum C, CC and CXC chemokine-binding protein. Serp-1 is a serine protease inhibitor (serpin) inhibiting thrombotic and thrombolytic pathways. Serp-1 also reduces arterial inflammation and improves survival in a mouse herpes virus (MHV68) model of lethal vasculitis. In addition, Serp-1 demonstrated safety and efficacy in patients with unstable coronary disease and stent implant, reducing markers of myocardial damage. We investigate here the effects of Porphyromonas gingivalis, a periodontal pathogen, on restenosis after BA and the effects of blocking chemokine and protease pathways with M-T7 and Serp-1. ApoE^−/− mice had aortic BA and oral P. gingivalis infection. Arterial plaque growth was examined at 24 weeks with and without anti-inflammatory protein treatment. Dental plaques from mice infected with P. gingivalis tested positive for infection. Neither Serp-1 nor M-T7 treatment reduced infection, but IgG antibody levels in mice treated with Serp-1 and M-T7 were reduced. P. gingivalis significantly increased monocyte invasion and arterial plaque growth after BA (P<0.025). Monocyte invasion and plaque growth were blocked by M-T7 treatment (P<0.023), whereas Serp-1 produced only a trend toward reductions. Both proteins modified expression of TLR4 and MyD88. In conclusion, aortic plaque growth in ApoE^−/− mice increased after angioplasty in mice with chronic oral P. gingivalis infection. Blockade of chemokines, but not serine proteases significantly reduced arterial plaque growth, suggesting a central role for chemokine-mediated inflammation after BA in P. gingivalis infected mice.     

趋化因子受体CXCR1、CXCR2与肿瘤研究进展

趋化因子受体是由7个跨膜区组成的G蛋白偶联受体,多个系统的肿瘤细胞均表达趋化因子受体,其在肿瘤的发生、发展和转移等各个阶段都发挥重要作用.近年来有不少研究发现趋化因子受体中的CXCR1和CXCR2与肿瘤关系密切,认为其可能成为肿瘤治疗的一个潜在新靶点.本文就CXCR1和CXCR2这两种趋化因子受体与肿瘤的关系做一综述.     

DNA甲基化调控炎症反应干预As斑块稳定性的研究进展

动脉粥样硬化(As)斑块破裂是导致急性心脑血管事件发生的首要原因。既往对斑块破裂的基础研究多集中于细胞和分子水平,从表观遗传学角度阐述的研究较少。DNA甲基化作为表观遗传学修饰的主要方式之一,可在不改变基因核苷酸序列的情况下影响基因的表达。综合目前研究来看,炎症反应在斑块破裂过程中起关键性作用,而DNA甲基化对炎症反应又起重要的调控作用。因此,改变DNA甲基化状态来调控炎症反应干预As斑块稳定性,有望成为防治As等心脑血管疾病的有效途径之一。本文主要围绕与As炎症反应密切相关的几种炎症免疫细胞及炎症因子等方面,对近年来DNA甲基化调控炎症反应干预As斑块稳定性的研究进展作一综述。     

不同剂量的阿托伐他汀对急性心肌梗死患者血管内皮功能及动脉粥样斑块稳定性的影响

目的:观察和比较不同剂量的阿托伐他汀对急性心肌梗死患者血管内皮功能及动脉粥样斑块稳定性的影响.方法:选择我院收治的急性心肌梗死患者56例,随机分为高剂量和低剂量阿托伐他汀治疗组,每组28例.高剂量组给予阿托伐他汀40 mg/d,低剂量组给予阿托伐他汀20mg/d治疗,检测和比较两组患者治疗前后血管舒张功能(FMD)、淋巴细胞刺激指数(SI)和IFN-γ水平的变化.结果:治疗前,两组患者的FMD、SI、IFN-γ水平比较均无统计学意义(均P＞0.05).治疗后,所有患者的FMD均较治疗前显著升高,差异均有统计学意义(低剂量组:t=1.098,P=0.025;高剂量组:t=2.053,P＝0.017),且高剂量组FMD显著高于低剂量组,差异有统计学意义(t=2.451,P=0.017);患者SI、IFN-γ水平均较治疗前降低,差异有统计学意义(均P＜0.05).高剂量组SI、IFN-γ均显著低于低剂量组,差异有统计学意义(SI:t=2.234,P=0.002; IFN-γ:t＝4.416,P＝0.001).结论:与低剂量阿托伐他汀相比,高剂量阿托伐他汀对急性心肌梗死患者血管内皮功能及炎性反应的改善作用更明显.     

The Viral KSHV Chemokine vMIP-II Inhibits the Migration of Naive and Activated Human NK Cells by Antagonizing Two Distinct Chemokine Receptors

Natural killer (NK) cells are innate immune cells able to rapidly kill virus-infected and tumor cells. Two NK cell populations are found in the blood; the majority (90%) expresses the CD16 receptor and also express the CD56 protein in intermediate levels (CD56^Dim CD16^Pos) while the remaining 10% are CD16 negative and express CD56 in high levels (CD56^Bright CD16^Neg). NK cells also reside in some tissues and traffic to various infected organs through the usage of different chemokines and chemokine receptors. Kaposi''s sarcoma-associated herpesvirus (KSHV) is a human virus that has developed numerous sophisticated and versatile strategies to escape the attack of immune cells such as NK cells. Here, we investigate whether the KSHV derived cytokine (vIL-6) and chemokines (vMIP-I, vMIP-II, vMIP-III) affect NK cell activity. Using transwell migration assays, KSHV infected cells, as well as fusion and recombinant proteins, we show that out of the four cytokine/chemokines encoded by KSHV, vMIP-II is the only one that binds to the majority of NK cells, affecting their migration. We demonstrate that vMIP-II binds to two different receptors, CX3CR1 and CCR5, expressed by naïve CD56^Dim CD16^Pos NK cells and activated NK cells, respectively. Furthermore, we show that the binding of vMIP-II to CX3CR1 and CCR5 blocks the binding of the natural ligands of these receptors, Fractalkine (Fck) and RANTES, respectively. Finally, we show that vMIP-II inhibits the migration of naïve and activated NK cells towards Fck and RANTES. Thus, we present here a novel mechanism in which KSHV uses a unique protein that antagonizes the activity of two distinct chemokine receptors to inhibit the migration of naïve and activated NK cells.     

Dcf1 Affects Memory and Anxiety by Regulating NMDA and AMPA Receptors

The hippocampus is critical for memory and emotion and both N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid (AMPA) receptors are known to contribute for those processes. However, the underlying molecular mechanisms remain poorly understood. We have previously found that mice undergo memory decline upon dcf1 deletion through ES gene knockout. In the present study, a nervous system-specific dcf1 knockout (NKO) mouse was constructed, which was found to present severely damaged neuronal morphology. The damaged neurons caused structural abnormalities in dendritic spines and decreased synaptic density. Decreases in hippocampal NMDA and AMPA receptors of NKO mice lead to abnormal long term potentiation (LTP) at DG, with significantly decreased performance in the water maze, elevated- plus maze, open field and light and dark test. Investigation into the underlying molecular mechanisms revealed that dendritic cell factor 1 (Dcf1) contributes for memory and emotion by regulating NMDA and AMPA receptors. Our results broaden the understanding of synaptic plasticity’s role in cognitive function, thereby expanding its known list of functions.

     

Physiological Function of Gastrin-Releasing Peptide and Neuromedin B Receptors in Regulating Itch Scratching Behavior in the Spinal Cord of Mice

Pruritus (itch) is a severe side effect associated with the use of drugs as well as hepatic and hematological disorders. Previous studies in rodents suggest that bombesin receptor subtypes i.e. receptors for gastrin-releasing peptide (GRPr) and neuromedin B (NMBr) differentially regulate itch scratching. However, to what degree spinal GRPr and NMBr regulate scratching evoked by intrathecally administered bombesin-related peptides is not known. The first aim of this study was to pharmacologically compare the dose-response curves for scratching induced by intrathecally administered bombesin-related peptides versus morphine, which is known to elicit itch in humans. The second aim was to determine if spinal GRPr and NMBr selectively or generally mediate scratching behavior. Mice received intrathecal injection of bombesin (0.01–0.3 nmol), GRP (0.01–0.3nmol), NMB (0.1–1nmol) or morphine (0.3–3 nmol) and were observed for one hour for scratching activity. Bombesin elicited most profound scratching over one hour followed by GRP and NMB, whereas morphine failed to evoke scratching response indicating the insensitivity of mouse models to intrathecal opioid-induced itch. Intrathecal pretreatment with GRPr antagonist RC-3095 (0.03–0.1 nmol) produced a parallel rightward shift in the dose response curve of GRP-induced scratching but not NMB-induced scratching. Similarly, PD168368 (1–3 nmol) only attenuated NMB but not GRP-induced scratching. Individual or co-administration of RC-3095 and PD168368 failed to alter bombesin-evoked scratching. A higher dose of RC-3095 (0.3 nmol) generally suppressed scratching induced by all three peptides but also compromised motor function in the rotarod test. Together, these data indicate that spinal GRPr and NMBr independently drive itch neurotransmission in mice and may not mediate bombesin-induced scratching. GRPr antagonists at functionally receptor-selective doses only block spinal GRP-elicited scratching but the suppression of scratching at higher doses is confounded by motor impairment.     

High-Frequency rTMS Improves Cognitive Function by Regulating Synaptic Plasticity in Cerebral Ischemic Rats

Neurochemical Research - Poststroke cognitive impairment (PSCI) is one of the most severe sequelae of stroke and lacks effective treatment. Previous studies have shown that high-frequency...     

阿托伐他汀联合普罗布考对动脉硬化家兔血流及斑块影响

目的:探讨阿托伐他汀钙片联合普罗布考治疗对兔颈动脉斑块稳定性的影响及血液流场改变。方法:选取清洁级日本大耳白兔40只,随机分为正常组、模型组、实验组、对照组,每组10只,复制颈动脉粥样硬化模型。对照组按照阿托伐他汀钙10 mg/(kg·d)的剂量,给兔按照不同体重予以不同药量治疗,将药物以生理盐水稀释至5 mL灌胃,实验组在对照组基础上加用普罗布考片0.25 g/(kg·d),与阿托伐他汀钙一同以生理盐水稀释至5 mL灌胃,模型组及正常组予以5 mL生理盐水灌胃。干预持续4周。用动物超声影像系统对兔进行颈动脉超声检查,彩色多普勒血流显像及血管成像检测颈动脉狭窄程度,血流速度,血流动力学改变。结果:1治疗后实验组阿托伐他汀钙片联合普罗布考治疗对兔颈动脉内-中膜厚度、斑块面积与模型组相比均明显改善,稳定斑块数明显增加,与对照组比较,实验组改善明显,差异有统计学意义(P0.05);2正常组颈动脉正常,治疗后,实验组狭窄明显减轻,血流速度接近正常,对照组有所改善,模型组颈动脉狭窄程度最重,血流速度快,血流动力学发生改变,斑块不稳定性增加,差异有统计学意义(P0.05)。结论:阿托伐他汀钙片联合普罗布考治疗能够有效提高兔颈动脉粥样硬化斑块的稳定性,改善颈动脉狭窄,使血液流速接近正常水平,值得做进一步药理研究及深入探讨。