The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses
The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses
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DOI：
10.1172/jci14002
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发表时间：
2001-10-01
影响因子：
15.9
通讯作者：
Stern, DM
中科院分区：
文献类型：
--
作者：
Schmidt, AM;Du Yan, S;Stern, DM
AGEs肿瘤生物学体外制备的两性白蛋白（7）。其细胞外结构域由三个免疫球蛋白样区域组成，一个“V”型，然后是两个“C”型（8）。它含有一个跨膜结构域和一个43个氨基酸的胞质尾。结构-功能研究表明，V结构域对于配体结合至关重要，胞质尾部对于RAGE介导的细胞内信号传导至关重要（图1）。一个截短的形式，它缺乏胞质尾部，仍然牢牢地嵌入在膜。尽管这种形式的受体能够结合RAGE配体的通常补体，但它作为显性负性（称为“DN-RAGE”）受体起作用，并且其表达显著抑制RAGE介导的信号传导，即使在携带全长形式的细胞中也是如此（9，10）。在正常组织和脉管系统中以低水平表达。然而，无论其配体在何处积累，受体都被上调（11-13）。例如，在糖尿病血管中，RAGE配体包括至少两种类型的AGEs、（羧甲基）赖氨酸加合物和氢咪唑酮（14）以及S100/钙颗粒蛋白。在糖尿病血管系统中，内皮细胞、平滑肌细胞和浸润单核吞噬细胞中的β-淀粉样蛋白表达增加。重叠表达的β-淀粉样蛋白及其配体使我们考虑的可能性，β-淀粉样蛋白介导的细胞激活糖尿病血管。事实上，细胞培养中的研究表明，AGE-E2相互作用改变了血管稳态中重要的细胞特性（15-17）。例如，在AGEs与血管内皮细胞结合后，内皮细胞增加了VCAM-1、组织因子和IL-6的表达，以及它们对大分子的渗透性（18-20）。AGE-β介导的转录因子NF-κB的活化可能至少部分解释了这些观察结果（20，21）。在单核吞噬细胞中，AGEs激活细胞因子和生长因子的表达，并诱导细胞迁移以响应可溶性AGEs，而固定化配体则发生趋触性（22）。这些考虑使我们提出了以下糖尿病血管中RAGE介导的细胞特性扰动的两次打击模型：RAGE的配体的存在改变了血管的特性，导致激活/功能障碍的基础状态（第一次命中;图2）;在叠加刺激下，例如氧化脂蛋白沉积、感染或局部缺血，细胞反应有利于血管功能紊乱和组织损伤，而不是恢复体内平衡（第二次打击;图2）。糖尿病大血管疾病提供了一个特别重要的情况来测试这个模型，因为流行病学研究表明，除了糖尿病和传统上与动脉粥样硬化相关的因素之外，其他因素也有助于发病机制。对于这些研究，我们最初的实验系统采用了用链脲佐菌素（一种导致胰岛素缺乏的β细胞毒素）治疗的动脉粥样硬化易感小鼠（C57 BL/6背景中的apoE缺失动物）（23）。与血糖正常的apoE基因缺失小鼠相比，糖尿病动物在14周龄时已经表现出明显的晚期动脉粥样硬化。载脂蛋白E缺失动物的糖尿病血管显示动脉粥样硬化病变的数量和面积增加，以及纤维帽、胆固醇裂隙和坏死的复杂性增强。糖尿病血管系统中AGEs和VEGF的水平增加，组织因子、VCAM-1和基质金属蛋白酶（MMP）2和9的表达也是如此。为了阻止-
AGEs Tumor biology Amphoterin albumin prepared in vitro (7). Its extracellular domain consists of three immunoglobulin-like regions, one “V”-type followed by two “C”-type (8). RAGE contains a single transmembrane-spanning domain and a 43–amino acid cytosolic tail. Structure-function studies have shown that the V-domain is critical for ligand binding and that the cytosolic tail is essential for RAGE-mediated intracellular signalling (Figure 1). A truncated form of RAGE, which lacks the cytosolic tail, remains firmly embedded in the membrane. Although this form of the receptor is competent to bind the usual complement of RAGE ligands, it acts as a dominant negative (termed “DN-RAGE”) receptor, and its expression strikingly suppresses RAGE-mediated signaling, even in cells bearing the full-length form (9, 10). RAGE is expressed at low levels in normal tissues and vasculature. However, the receptor becomes upregulated wherever its ligands accumulate (11–13). In diabetic vessels, for example, RAGE ligands include AGEs of at least two types,(carboxymethyl) lysine adducts and hydroimidazolones (14), and S100/calgranulins as well. RAGE expression is increased in endothelium, smooth muscle cells, and infiltrating mononuclear phagocytes in diabetic vasculature. The overlapping expression of RAGE and its ligands led us to consider the possibility that RAGE mediates cellular activation in diabetic vessels. Indeed, studies in cell culture show that AGE-RAGE interaction alters cellular properties important in vascular homeostasis (15–17). For example, following engagement of RAGE by AGEs, endothelia increase their expression of VCAM-1, tissue factor, and IL-6, and their permeability to macromolecules (18–20). AGE-RAGE–mediated activation of the transcription factor NF-κB is likely to explain these observations, at least in part (20, 21). In mononuclear phagocytes, RAGE activates expression of cytokines and growth factors and induces cell migration in response to soluble AGEs, whereas haptotaxis occurs with immobilized ligands (22). These considerations led us to propose the following two-hit model for RAGE-mediated perturbation of cellular properties in diabetic vasculature: the presence of ligands for RAGE changes properties of the vasculature, resulting in a basal state of activation/dysfunction (first hit; Figure 2); with a superimposed stimulus, such as deposition of oxidized lipoproteins, infection, or ischemia, cellular responses favor derangement of vascular function and tissue damage, rather than restitution of homeostasis (second hit; Figure 2). Diabetic macrovascular disease provides an especially important situation to test this model, as epidemiologic studies have suggested that factors other than glycemia and those traditionally associated with atherosclerosis contribute to pathogenesis. For these studies, our initial experimental system employed atherosclerosis-prone mice (apoE-null animals in the C57BL/6 background) treated with streptozotocin (23), a β-cell toxin that causes insulin deficiency. In contrast to euglycemic apoE-null mice, diabetic animals display advanced atherosclerosis already evident by 14 weeks of age. Diabetic vasculature in the apoE-null animals shows an increased number and area of atherosclerotic lesions, as well as enhanced complexity, with fibrous caps, cholesterol clefts, and necrosis. Levels of AGEs and RAGE are increased in diabetic vasculature, as is expression of tissue factor, VCAM-1, and matrix metalloproteinases (MMPs) 2 and 9. To deter-