Purinergic modulation of the autoimmune vascular phenotype

自身免疫血管表型的嘌呤能调节

• 批准号: 10168724
• 负责人: Jason Knight
• 金额: $ 15.6万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2022-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10168724
• 关键词: Adenosine; Agonist; Anti-Inflammatory Agents; Antiphospholipid Antibodies; Atherosclerosis; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Automobile Driving; Blood Platelets; Blood Vessels; Blood coagulation; Bone Marrow; Cells; Cessation of life; Chromatin; Clinical; Coagulation Process; Data; Disease; Endothelial Cells; Endothelium; Enzymes; Event; Fibrinolytic Agents; Functional disorder; Genetic Models; Goals; Human; Hydrocarbons; In Situ; In Vitro; Inflammation; Intervention; Knock-out; Laboratories; Leukocytes; Lupus; Mediating; Mediator of activation protein; Minority; Modeling; Mus; Myocardial Infarction; Neurofibrillary Tangles; Neutrophil Activation; Neutrophil Infiltration; Oxidative Stress; Pathway interactions; Patients; Phenotype; Pristane; Purine Nucleotides; Purinergic P1 Receptors; Purinoceptor; Relaxation; Respiratory Burst; Signal Pathway; Signal Transduction; Stroke; Surface; Systemic Lupus Erythematosus; Therapeutic; Thrombosis; Thrombus; Tissues; Venous; Venous Thrombosis; Wild Type Mouse; Woman; Work; differential expression; endothelial dysfunction; experience; experimental study; extracellular; inflammatory milieu; insight; lupus prone mice; mouse model; neutrophil; novel; novel strategies; prevent; receptor; reconstitution; targeted treatment; thromboinflammation; vasoconstriction

ABSTRACT Dead and dying cells release purine nucleotides, which engage purinergic receptors on the surfaces of leukocytes, platelets, and vascular cells to trigger inflammation, coagulation, and vasoconstriction. To counter these mediators of vascular disequilibrium, leukocytes and endothelial cells express surface ectonucleotidases (CD39 and CD73), which catalyze the step-wise phosphohydrolysis of ATP into adenosine—thereby creating an anti-inflammatory, antithrombotic “halo” around the cell. In patients with systemic lupus erythematosus (commonly referred to as “lupus”), stroke and venous thrombosis are relentlessly driven by oxidative stress and prothrombotic autoantibodies. Furthermore, our laboratory recently discovered that neutrophil extracellular traps (NETs, tangles of chromatin expelled by “NETosis”) trigger endothelial damage and in situ thrombosis in lupus. Our preliminary data now reveal that, in lupus, CD73 counteracts neutrophil infiltration, NETosis, dysfunction of the arterial endothelium, and venous thrombosis. The hypothesis driving this work is that CD73 and its downstream pathways serve as an endogenous (and potentially amplifiable) counterpoint to thrombo- inflammatory events in lupus. The Aims of this project are to: (1) Elucidate cell- and receptor-specific mechanisms by which CD73 protects against lupus-mediated dysfunction of the arterial endothelium. In addition to two traditional models of murine lupus, we will use a novel approach whereby the administration of human lupus autoantibodies into mice rapidly triggers endothelial dysfunction. Endpoints will determine the mechanism(s) by which CD73 and adenosine receptors (A2A, A2B, A3) thwart arterial inflammation and endothelial dysfunction in lupus-prone mice, and will define the extent to which lineage-specific expression of CD73 (neutrophils vs. endothelium) guards against these phenotypes. Endpoints will also globally assess the deranged autoimmune/inflammatory milieu of lupus. (2) Ascertain how CD73 and downstream purinergic signaling modulate lupus-mediated venous thrombosis. Experiments will again leverage traditional models of murine lupus, as well as a novel model whereby human lupus autoantibodies markedly potentiate venous thrombosis in mice. We will determine the extent to which lineage-specific expression of CD73 protects against venous thrombosis, and will elucidate mechanism(s) by which CD73 and adenosine receptors mitigate autoantibody-mediated NETosis. Overall, these studies should yield new insight into how a pathway that functions as an endogenous guardian against inflammation may be exploited to counteract the relentless thrombo-inflammatory course of lupus.

摘要 死亡和垂死的细胞释放嘌呤核苷酸，这些核苷酸与细胞表面的嘌呤能受体结合 白血球、血小板和血管细胞引发炎症、凝血和血管收缩。去反击 这些血管失衡的介质、白细胞和内皮细胞表达表面胞外核苷酸酶。 (CD39和CD73)，它催化ATP逐步磷酸水解为腺苷-从而产生 细胞周围有一个抗炎、抗血栓的“光环”。系统性红斑狼疮患者 (通常称为“狼疮”)，中风和静脉血栓形成是由氧化应激无情地驱动的。 和血栓前自身抗体。此外，我们实验室最近发现，中性粒细胞胞外 陷阱(网，“网状结构”排出的染色质缠结)引发血管内皮细胞损伤和原位血栓形成。 狼疮。我们的初步数据现在显示，在狼疮中，CD73可以抵消中性粒细胞的渗透，网织， 动脉内皮功能障碍和静脉血栓形成。推动这项工作的假设是CD73 它的下游通路是血栓形成的内源性(而且可能是可放大的)对应物。 狼疮中的炎性事件。 这个项目的目的是：(1)阐明CD73保护细胞和受体的特定机制 抗狼疮所致的动脉内皮功能障碍。除了两种传统的小鼠模型 狼疮，我们将使用一种新的方法，将人类狼疮自身抗体注射到小鼠体内 迅速引发内皮功能障碍。端点将决定CD73和CD73的机制(S) 腺苷受体(A2A、A2B、A3)抑制狼疮易感小鼠动脉炎症和内皮功能障碍 并将确定CD73(中性粒细胞与内皮细胞)的谱系特异性表达在多大程度上保护 来对抗这些表型。终端还将在全球范围内评估错乱的自身免疫/炎症环境 狼疮的症状。(2)确定CD73及其下游的嘌呤能信号如何调节狼疮介导的静脉 血栓形成。实验将再次利用传统的小鼠狼疮模型以及一种新的模型 人类狼疮自身抗体可显著增强小鼠的静脉血栓形成。我们将确定 CD73的谱系特异性表达在多大程度上保护静脉血栓形成，并将阐明 CD73和腺苷受体减轻自身抗体介导的NET中毒的机制(S)。 总体而言，这些研究应该会对作为内源性守护者的一条途径如何发挥作用产生新的见解 抗炎症可能被用来对抗狼疮持续的血栓炎症过程。