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，嘌呤核苷酸与细胞表面的嘌呤能受体结合， 白细胞、血小板和血管细胞以引发炎症、凝血和血管收缩。打击 这些血管不平衡介质、白细胞和内皮细胞表达表面外核苷酸酶 (CD39和CD 73），其催化ATP逐步磷酸化水解为腺苷，从而产生 细胞周围的抗炎、抗血栓“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，我们的实验室最近发现， 陷阱（NETs，由“NETosis”排出的染色质缠结）触发内皮损伤和原位血栓形成， 狼疮我们的初步数据显示，在狼疮中，CD 73抵消了中性粒细胞浸润，NETosis， 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，CD 73 其下游通路作为血栓的内源性（和潜在的可消除的）对应点， 狼疮的炎症反应 本研究的目的是：（1）阐明CD 73保护细胞和受体的特异性机制， 对抗狼疮介导的动脉内皮功能障碍。除了两种传统的小鼠模型外， 我们将使用一种新的方法，将人类狼疮自身抗体注入小鼠体内， 迅速引发内皮功能障碍。终点将决定CD 73和CD 40表达的机制。 腺苷受体（A2 A、A2 B、A3）在狼疮易感小鼠中阻碍动脉炎症和内皮功能障碍， 并将确定CD 73（中性粒细胞与内皮细胞）的谱系特异性表达的保护程度 针对这些表型。终点还将全面评估紊乱的自身免疫性/炎症环境 狼疮(2)确定CD 73和下游嘌呤能信号传导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， 由此人狼疮自身抗体显著增强小鼠中的静脉血栓形成。康贝特人将以 CD 73的谱系特异性表达在多大程度上防止静脉血栓形成，并将阐明 CD 73和腺苷受体减轻自身抗体介导的NETosis的机制。 总的来说，这些研究应该产生新的见解，如何作为一个内源性监护人的途径， 可以用来对抗狼疮的无情的血栓炎症过程。