Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity.
Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity.
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DOI：
10.1161/circresaha.110.223875
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发表时间：
2011-01-21
影响因子：
20.1
通讯作者：
Witztum JL
中科院分区：
文献类型：
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作者：
Miller YI;Choi SH;Wiesner P;Fang L;Harkewicz R;Hartvigsen K;Boullier A;Gonen A;Diehl CJ;Que X;Montano E;Shaw PX;Tsimikas S;Binder CJ;Witztum JL
氧化反应是新陈代谢和信号转导的重要组成部分。然而，它们也会产生活性氧，从而损害脂质、蛋白质和 DNA，产生“氧化特异性”表位。在这篇综述中，我们将讨论这样的假设：这种常见的氧化特异性表位是先天免疫的主要目标，可以被多种“模式识别受体”（PRR）识别。通过与微生物“病原体相关分子模式”（PAMP）进行类比，我们假设宿主衍生的氧化特异性表位可以被认为代表“危险（或损害）相关分子模式”（DAMP）。我们还认为，凋亡细胞及其细胞碎片上存在的氧化特异性表位为选择此类 PRR 提供了主要的进化压力。此外，由于微生物上的许多 PAMP 与氧化特异性表位具有相同的分子同一性和/或模拟性，因此此类 PAMP 也为同一组氧化特异性 PRR 提供了强大的二次选择压力。由于脂质过氧化是普遍存在的，并且是与动脉粥样硬化相关的炎症状态的主要组成部分，因此了解氧化特异性表位是 DAMP，因此是先天免疫多个弧的目标，为动脉粥样硬化的发病机制提供了新的见解。作为例子，我们证明细胞和可溶性 PRR，如 CD36、Toll 样受体 4、天然抗体和 CRP 都能识别常见的氧化特异性 DAMP，如氧化磷脂和氧化胆固醇酯，并介导多种免疫反应，从促炎基因的表达到细胞内脂蛋白过度积累，再到动脉粥样硬化保护性体液免疫。这些见解可能会提高对炎症和动脉粥样硬化形成的理解，并提出新的诊断和治疗方法。
Oxidation reactions are vital parts of metabolism and signal transduction. However, they also produce reactive oxygen species, which damage lipids, proteins and DNA, generating “oxidation-specific” epitopes. In this review, we will discuss the hypothesis that such common oxidation-specific epitopes are a major target of innate immunity, recognized by a variety of “pattern recognition receptors” (PRRs). By analogy with microbial “pathogen associated molecular patterns” (PAMPs), we postulate that host-derived, oxidation-specific epitopes can be considered to represent “danger (or damage) associated molecular patterns” (DAMPs). We also argue that oxidation-specific epitopes present on apoptotic cells and their cellular debris provided the primary evolutionary pressure for the selection of such PRRs. Further, because many PAMPs on microbes share molecular identity and/or mimicry with oxidation-specific epitopes, such PAMPs provided a strong secondary selecting pressure for the same set of oxidation-specific PRRs as well. Because lipid peroxidation is ubiquitous and a major component of the inflammatory state associated with atherosclerosis, the understanding that oxidation-specific epitopes are DAMPs, and thus the target of multiple arcs of innate immunity, provides novel insights into the pathogenesis of atherosclerosis. As examples, we show that both cellular and soluble PRRs, such as CD36, toll-like receptor-4, natural antibodies, and CRP recognize common oxidation-specific DAMPs, such as oxidized phospholipids and oxidized cholesteryl esters, and mediate a variety of immune responses, from expression of proinflammatory genes to excessive intracellular lipoprotein accumulation to atheroprotective humoral immunity. These insights may lead to improved understanding of inflammation and atherogenesis and suggest new approaches to diagnosis and therapy.