Impairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation.
Impairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation.
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DOI：
10.1161/atvbaha.111.224709
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发表时间：
2011-05
期刊：
影响因子：
--
通讯作者：
Lichtman AH
中科院分区：
文献类型：
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作者：
Bu DX;Tarrio M;Maganto-Garcia E;Stavrakis G;Tajima G;Lederer J;Jarolim P;Freeman GJ;Sharpe AH;Lichtman AH
程序性细胞死亡-1(PD-1)是CD28超家族中的一员，它在与其两个配体PD-L1或PD-L2相互作用时传递负信号。我们研究了PD-1通路在调节促进动脉粥样硬化病变形成和炎症的T细胞中的作用。我们发现，与Ldlr−/−对照组小鼠相比，−/−Ldlr−/−小鼠出现了更大的皮损，有更多的CD4+和CD8+T细胞和巨噬细胞，并伴随着更高水平的血清肿瘤坏死因子-α。与对照组相比，pd1−/−ldlr−/−小鼠的髂淋巴结T细胞在低密度脂蛋白CD3或氧化低密度脂蛋白的刺激下增殖更多。在体内和体外，来自pd1−/−ldlr−/−小鼠的CD8+T细胞显示出比对照组更强的细胞毒活性。给予封闭的抗PD-1抗体增加了高胆固醇血症LDLR−/−小鼠的皮损炎症，这些小鼠的皮损T细胞更多，主动脉旁淋巴结中的T细胞更活跃。在缺乏PD-L1和PD-L2造血细胞的骨髓嵌合LDLR−/−小鼠中，也观察到PD-1缺失或被阻断时T细胞含量的变化。PD-1在下调致动脉粥样硬化的T细胞反应中具有重要作用，阻断该分子用于治疗病毒感染或癌症可能会增加心血管并发症的风险。
Programmed cell death-1 (PD-1) is a member of the CD28 superfamily that delivers negative signals upon interaction with its two ligands, PD-L1 or PD-L2. We studied the contribution of PD-1 pathway in regulating T cells that promote atherosclerotic lesion formation and inflammation. We show that compared to Ldlr−/− control mice, Pd1−/−Ldlr−/− mice developed larger lesions with more abundant CD4+ and CD8+ T cells and macrophages, accompanied by higher levels of serum TNF-α. Iliac lymph node T cells from Pd1−/−Ldlr−/− mice proliferated more to αCD3 or oxidized LDL stimulation compared to controls. CD8+ T cells from Pd1−/−Ldlr−/− mice display more cytotoxic activity, compared to controls in vivo and in vitro. Administration of a blocking anti-PD-1 antibody increased lesional inflammation in hypercholesterolemic Ldlr−/− mice with more lesional T cells, and more activated T cells in paraaortic lymph nodes. The changes in lesional T cell content when PD-1 was absent or blocked were also observed in bone marrow chimeric Ldlr−/− mice lacking PD-L1 and PD-L2 on hematopoietic cells. PD-1 has an important role in down-regulating proatherogenic T cell responses, and blockade of this molecule for treatment of viral infections or cancer may increase risk for cardiovascular complications.