Ecto-5' nucleotidase (CD73)-mediated adenosine generation and signaling in murine cardiac allograft vasculopathy.
Ecto-5' nucleotidase (CD73)-mediated adenosine generation and signaling in murine cardiac allograft vasculopathy.
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DOI：
10.1161/circresaha.108.180059
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发表时间：
2008-12-05
影响因子：
20.1
通讯作者：
Pinsky DJ
中科院分区：
文献类型：
--
作者：
Hasegawa T;Bouïs D;Liao H;Visovatti SH;Pinsky DJ
Ecto-5'-核苷酸酶 (CD73) 催化 5'-单磷酸腺苷的末端磷酸水解，并在内皮细胞上广泛表达，调节屏障功能。由于它也在淋巴细胞上表达，我们假设它调节稳态条件下的血管免疫调节和心脏同种异体移植等应激条件下的失调。在异位心脏同种异体移植模型中，供体或受体的 CD73 缺乏导致移植物存活率降低和心脏同种异体移植血管病 (CAV) 的发展，表明 CD73 在血管病发病机制中对移植物驻留细胞和循环细胞都有贡献。缺乏 CD73 引起的血管紊乱包括移植物屏障功能丧失和 A2B 腺苷受体 (A2BAR) 移植物表达减少，同时急性炎症和免疫反应加剧。 CD73 在调节内皮-淋巴细胞相互作用中的重要性在异种匹配的体外共培养实验中得到了进一步证明。 CD73 的基因缺失或药理学阻断都会增加跨内皮淋巴细胞迁移和炎症反应，表明 CD73 通过其酶活性在抑制跨内皮白细胞运输方面发挥着关键作用。此外，A2BAR的拮抗作用导致血管渗漏显着增加，并且A2BAR的激动作用导致移植物存活显着延长并抑制CAV发展。这些数据提出了一种新的范例，其中移植物驻留细胞或循环细胞上的 CD73 对单磷酸腺苷的磷酸水解减少了跨内皮白细胞运输，并通过 A2BAR 减轻了心脏移植的炎症和免疫后遗症。
Ecto-5′-nucleotidase (CD73) catalyzes the terminal phosphohydrolysis of 5′-adenosine monophosphate, and is widely expressed on endothelial cells where it regulates barrier function. As it is also expressed on lymphocytes, we hypothesized that it modulates vascular immune regulation under homeostatic conditions and dysregulation under stress conditions such as cardiac allotransplantation. In a heterotopic cardiac allotransplantation model, CD73 deficiency in either donors or recipients resulted in decreased graft survival and the development of cardiac allograft vasculopathy (CAV), suggesting a contribution of CD73 on both graft-resident and circulating cells in vasculopathy pathogenesis. Vascular perturbations incited by lack of CD73 included loss of graft barrier function, and diminished graft expression of the A2B adenosine receptor (A2BAR), with a concordant exacerbation of the acute inflammatory and immune responses. The importance of CD73 in modulating endothelial-lymphocyte interaction was further demonstrated in allomismatched in vitro coculture experiments. Either genetic deletion or pharmacological blockade of CD73 increased transendothelial lymphocyte migration and inflammatory responses, suggesting that CD73 plays a critical role to suppress transendothelial leukocyte trafficking through its enzymatic activity. In addition, antagonism of A2BAR caused a significant increase in vascular leakage, and agonism of A2BAR resulted in marked prolongation of graft survival and suppression of CAV development. These data suggest a new paradigm in which phosphohydrolysis of adenosine monophosphate by CD73 on graft-resident or circulating cells diminishes transendothelial leukocyte trafficking and mitigates inflammatory and immune sequelae of cardiac transplantation via the A2BAR.