Indoleamine 2,3-dioxygenase-1 is protective in atherosclerosis and its metabolites provide new opportunities for drug development
Indoleamine 2,3-dioxygenase-1 is protective in atherosclerosis and its metabolites provide new opportunities for drug development
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DOI：
10.1073/pnas.1517820112
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发表时间：
2015-10-20
影响因子：
11.1
通讯作者：
Monaco, Claudia
中科院分区：
文献类型：
--
作者：
Cole, Jennifer E.;Astola, Nagore;Monaco, Claudia
动脉粥样硬化是心血管疾病（CVD）的主要原因，心血管疾病是全球死亡的主要原因。尽管动脉粥样硬化中的脂质异常受到关注，但很明显免疫系统也具有重要的促动脉粥样硬化和抗动脉粥样硬化功能。吲哚胺-2，3-双加氧酶（IDO）催化必需氨基酸色氨酸降解为免疫调节代谢物。IDO缺乏如何影响动脉粥样硬化形成过程中的免疫反应尚不清楚，我们在小鼠和人动脉粥样硬化模型中探索了潜在的机制。高胆固醇血症ApoE（-/-）小鼠中IDO缺乏导致病变大小和斑块易损性的替代标志物显著增加。胆固醇水平未观察到显著变化，但在IDO缺陷型ApoE（-/-）小鼠的外周血、脾和淋巴结B细胞中发现IL-10产生减少。3，4-二甲氧基肉桂酰基邻氨基苯甲酸（3，4-DAA）是色氨酸代谢物邻氨基苯甲酸的口服活性合成衍生物，但不是L-犬尿氨酸，其增强培养的脾B细胞中IL-10的产生。最后，3，4-DAA治疗减少了ApoE（-/-）小鼠中颈诱导的动脉损伤后的病变形成和炎症，并减少了离体人动脉粥样硬化细胞培养物中细胞因子和趋化因子的产生。我们的数据表明，色氨酸代谢产物通过IDO的内源性生产是一个重要的反馈回路，控制动脉粥样硬化和动脉粥样硬化炎症。我们发现IDO通路在体内和体外诱导B细胞产生IL-10，这表明IDO可能在动脉粥样硬化中诱导B细胞的免疫调节功能。邻氨基苯甲酸衍生物在动脉粥样硬化中的良好作用为CVD的治疗提供了新的途径。
Atherosclerosis is the major cause of cardiovascular disease (CVD), the leading cause of death worldwide. Despite much focus on lipid abnormalities in atherosclerosis, it is clear that the immune system also has important pro- and antiatherogenic functions. The enzyme indoleamine-2,3-dioxygenase (IDO) catalyses degradation of the essential amino acid tryptophan into immunomodulatory metabolites. How IDO deficiency affects immune responses during atherogenesis is unknown and we explored potential mechanisms in models of murine and human atherosclerosis. IDO deficiency in hypercholesterolemic ApoE(-/-) mice caused a significant increase in lesion size and surrogate markers of plaque vulnerability. No significant changes in cholesterol levels were observed but decreases in IL-10 production were found in the peripheral blood, spleen and lymph node B cells of IDO-deficient compared with IDO-competent ApoE(-/-) mice. 3,4,-Dimethoxycinnamoyl anthranilic acid (3,4-DAA), an orally active synthetic derivative of the tryptophan metabolite anthranilic acid, but not L-kynurenine, enhanced production of IL-10 in cultured splenic B cells. Finally, 3,4-DAA treatment reduced lesion formation and inflammation after collar-induced arterial injury in ApoE(-/-) mice, and reduced cytokine and chemokine production in ex vivo human atheroma cell cultures. Our data demonstrate that endogenous production of tryptophan metabolites via IDO is an essential feedback loop that controls atherogenesis and athero-inflammation. We show that the IDO pathway induces production of IL-10 in B cells in vivo and in vitro, suggesting that IDO may induce immunoregulatory functions of B cells in atherosclerosis. The favorable effects of anthranilic acid derivatives in atherosclerosis indicate a novel approach toward therapy of CVD.