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J Immunol:同济大学杜昌升教授研究组揭示嘌呤受体P2Y12在调控Th17分化及自身免疫疾病中的功能

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摘要 : 2017年5月17日,国际免疫学杂志《The Journal of Immunology》上在线发表了同济大学生命科学与技术学院杜昌升教授研究组题为“Critical Role of P2Y12 Receptor in Regulation of Th17 Differentiation and Experimental Autoimmune Encephalomyelitis Pathogenesis”的研究论文。
2017年5月17日,国际免疫学杂志《The Journal of Immunology》上在线发表了同济大学生命科学与技术学院杜昌升教授研究组题为“Critical Role of P2Y12 Receptor in Regulation of Th17 Differentiation and Experimental Autoimmune Encephalomyelitis Pathogenesis”的研究论文。论文利用基因干预及药物干预的手段揭示了P2Y12 受体参与调控多发性硬化症(Multiple sclerosis, MS)等自身免疫疾病的发病过程。论文的第一作者为硕士生覃朝燕和博士生周金凤同学,杜昌升教授为论文通讯作者。 多发性硬化症(MS)是一种免疫细胞介导的脱髓鞘性神经退行性自身免疫病,其病理特征为髓鞘脱失,神经元损伤,炎症细胞浸润;其发病表现为视觉障碍、肢体无力、平衡感失调等。但到目前为止其内在的发病机制尚未完全阐明,治疗手段有限,因此研究和发现新的治疗靶点对MS的治疗非常关键。实验性自身免疫性脑脊髓炎(Experimental autoimmune encephalomyelitis, EAE)是研究MS的理想模型。其发病原理主要为T细胞、尤其是致病性的Th1和Th17在免疫系统的过度激活所导致的神经系统的炎症反应,发病病理学和组织学特征与MS基本一致。 g蛋白偶联受体(G protein–coupled receptors, GPCRs)是人体内最大的蛋白质受体家族,参与许多生物反应及人类疾病的信号转导过程,是疾病治疗的重要药物靶点,P2Y12受体也是一种GPCR受体,隶属于嘌呤P2受体家族。本研究发现,在EAE发病过程中,P2Y12受体的表达量上调,预示着P2Y12受体可能在EAE的发病中具有重要作用。进一步研究证实,P2Y12敲除小鼠的EAE发病症状与野生型对照小鼠相比明显减轻,且外周免疫器官中致病性的Th17细胞减少。进一步的研究发现通过受体拮抗剂阻断P2Y12功能,可以很好的环节疾病小鼠的症状。通过T细胞的体外分化实验证明了敲除P2Y12能够抑制CD4+ T细胞向致病性Th17细胞的分化。更有趣的是,基于TNBS(2,4,6-trinitrobenzenesulfonic acid)诱导的肠炎和STZ(Streptozocin)诱导的I型糖尿病小鼠模型的研究进一步发现,利用基因敲除以及药物阻断的方式抑制P2Y12受体,能够显著减轻TNBS诱导的肠炎以及STZ诱导I型糖尿病的发病。本研究揭示了P2Y12受体在Th17细胞分化、及T细胞介导的自身免疫病的发病过程中的调控作用,受体拮抗剂对于模型小鼠有着显著的治疗作用,这提示P2Y12可能作为治疗多发性硬化症,自身免疫性肠炎以及一型糖尿病等自身免疫疾病的潜在药物靶点。 J Immunol:同济大学杜昌升教授研究组揭示嘌呤受体P2Y12在调控Th17分化及自身免疫疾病中的功能
图1:P2Y12通过外周免疫系统调控多发性硬化症的发病

原文链接:
Critical Role of P2Y12 Receptor in Regulation of Th17 Differentiation and Experimental Autoimmune Encephalomyelitis PathoGENEsis 原文摘要: Adenosine 5'-diphosphate is a key endogenous cell-signaling molecule that can activate P2 purinergic receptor family members. ADP-P2Y signaling is reported to be associated with inflammation, but its function in T cell differentiation and autoimmune diseases pathogenesis is unclear. In this study, we found that the P2Y12 receptor was upregulated in the peripheral immune tissues of experimental autoimmune encephalomyelitis (EAE) mice. Deficiency of P2Y12 led to a reduced peak severity and cumulative disease score in EAE mice, followed by a dramatic reduction of leukocyte infiltration and less extensive demyelination. The percentage of Th17, one of the main pathogenic T cells in EAE, was sharply decreased in P2Y12 knockout mice, accompanied by decreased IL-17A production and a low mRNA level of Th17-related genes. In vitro culture assay further verified that P2Y12 directly regulated Th17 differentiation. More interestingly, clopidogrel and ticagrelor, two P2Y12-specific antagonists, effectively alleviated the disease severity of EAE and inhibited Th17 differentiation both in vivo and in vitro. Further study demonstrated that blocking the P2Y12 receptor also ameliorated the symptoms of 2,4,6-trinitrobenzenesulfonic acid–induced colitis and multiple low-dose streptozocin-induced type 1 diabetes. Our findings not only revealed the critical role of P2Y12 in Th17 differentiation and EAE pathogenesis, but also suggested the promising potential of P2Y12 antagonists in the treatment of autoimmune diseases. doi:10.4049/jimmunol.1601549 作者:杜昌升 点击:
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