Cole Jennifer E, Astola Nagore, Cribbs Adam P, Goddard Michael E, Park Inhye, Green Patricia, Davies Alun H, Williams Richard O, Feldmann Marc, Monaco Claudia
Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Headington, Oxford OX3 7FY, United Kingdom;
Imperial Vascular Unit, Division of Surgery and Cancer, Imperial College, London W6 8RF, United Kingdom.
Proc Natl Acad Sci U S A. 2015 Oct 20;112(42):13033-8. doi: 10.1073/pnas.1517820112. Epub 2015 Oct 5.
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.
动脉粥样硬化是心血管疾病（CVD）的主要病因，而心血管疾病是全球首要死因。尽管动脉粥样硬化中脂质异常备受关注，但免疫系统显然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产物。IDO缺乏如何影响动脉粥样硬化发生过程中的免疫反应尚不清楚，我们在小鼠和人类动脉粥样硬化模型中探索了潜在机制。高胆固醇血症ApoE(-/-)小鼠中IDO缺乏导致病变大小显著增加以及斑块易损性替代标志物增加。未观察到胆固醇水平有显著变化，但与具有IDO功能的ApoE(-/-)小鼠相比，IDO缺乏小鼠的外周血、脾脏和淋巴结B细胞中IL-10产生减少。3,4-二甲氧基肉桂酰邻氨基苯甲酸（3,4-DAA）是色氨酸代谢产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，可增强培养的脾脏B细胞中IL-10的产生。最后，3,4-DAA治疗可减少ApoE(-/-)小鼠套环诱导的动脉损伤后的病变形成和炎症，并减少体外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，通过IDO内生产生色氨酸代谢产物是控制动脉粥样硬化和动脉粥样硬化炎症的重要反馈回路。我们表明，IDO途径在体内和体外均可诱导B细胞产生IL-10，提示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有利作用表明了一种治疗心血管疾病的新方法。
