From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream To Identify Novel Targets for Atheroprotection.
From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream To Identify Novel Targets for Atheroprotection.
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DOI：
10.1161/circresaha.115.306656
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发表时间：
2016-01-08
影响因子：
20.1
通讯作者：
Ridker PM
中科院分区：
文献类型：
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作者：
Ridker PM
炎症生物标志物高敏 C 反应蛋白 (hsCRP) 的血浆水平可以预测血管风险，其效果估计与总胆固醇或高密度脂蛋白胆固醇的效果一样大。此外，针对 hsCRP 的随机试验数据对于了解他汀类药物治疗的抗炎作用至关重要，并且一致证明治疗中 hsCRP 水平与治疗中 LDL 胆固醇水平一样，是残余心血管风险的有力预测因子。然而，虽然 hsCRP 在临床上可作为风险预测的生物标志物，但大多数机制研究表明 CRP 本身不太可能成为干预目标。从 CRP 到 IL-6 再到 IL-1 的炎症级联向上游移动，为动脉粥样硬化保护提供了新的治疗机会，重点关注中央 IL-6 信号系统，并最终抑制产生 IL-1β 的 NLRP3 炎症小体。胆固醇晶体、中性粒细胞胞外陷阱 (NET)、动脉粥样硬化流和局部组织缺氧会激活 NLRP3 炎症小体。因此，hsCRP 作为上游 IL-1β 活性下游替代生物标志物的统一概念已经出现。从治疗角度来看，小局部缺血研究表明，IL-1 受体拮抗剂阿那白滞素和 IL-6 受体阻滞剂托珠单抗可减少急性期 hsCRP 的产生。在高血管风险糖尿病患者中进行的一项 IIb 期研究表明，canakinumab（一种靶向 IL-1β 的人单克隆抗体）可显着降低血浆 IL-6、hsCRP 和纤维蛋白原水平，且不会改变致动脉粥样硬化脂质。卡那奴单抗目前正在一项随机试验中进行测试，该试验纳入了 10,065 名 hsCRP 升高的心肌梗塞后患者，该试验已全部入组，预计将于 2017 年完成。使用对 CRP/IL-6/IL-1 轴有效的替代抗炎药物（包括低剂量甲氨蝶呤和秋水仙碱）的临床试验正在探索中。如果成功，这些试验将关闭动脉粥样硬化炎症假说的循环，并作为如何将基本生物学原理转化为个性化医疗实践的例子。
Plasma levels of the inflammatory biomarker high sensitivity C-reactive protein (hsCRP) predict vascular risk with an effect estimate as large as that of total or HDL cholesterol. Further, randomized trial data addressing hsCRP have been central to understanding the anti-inflammatory effects of statin therapy and have consistently demonstrated on-treatment hsCRP levels to be as powerful a predictor of residual cardiovascular risk as on-treatment levels of LDL cholesterol. Yet, while hsCRP is clinically useful as a biomarker for risk prediction, most mechanistic studies suggest that CRP itself is unlikely to be a target for intervention. Moving upstream in the inflammatory cascade from CRP to IL-6 to IL-1 provides novel therapeutic opportunities for atheroprotection that focus on the central IL-6 signaling system and ultimately on inhibition of the IL-1β producing NLRP3 inflammasome. Cholesterol crystals, neutrophil extracellular traps (NETs), atheroprone flow, and local tissue hypoxia activate the NLRP3 inflammasome. As such, a unifying concept of hsCRP as a downstream surrogate biomarker upstream IL-1β activity has emerged. From a therapeutic perspective, small ischemia studies show reductions in acute phase hsCRP production with the IL-1 receptor antagonist anakinra and the IL-6 receptor blocker tocilizumab. A phase IIb study conducted among diabetic patients at high vascular risk indicates that canakinumab, a human monoclonal antibody that targets IL-1β, markedly reduces plasma levels of IL-6, hsCRP, and fibrinogen with no change in atherogenic lipids. Canakinumab in now being tested as a method to prevent recurrent cardiovascular events in a randomized trial of 10,065 post-myocardial infarction patients with elevated hsCRP that is fully enrolled and due to complete in 2017. Clinical trials employing alternative anti-inflammatory agents active against the CRP/IL-6/IL-1 axis including low dose methotrexate and colchicine are being explored. If successful, these trials will close the loop on the inflammatory hypothesis of atherosclerosis and serve as examples of how fundamental biologic principles can be translated into personalized medical practice.