Role of IgE in Atherosclerosis

描述（由申请人提供）：免疫球蛋白E （IgE）与过敏反应有关，但我们发现急性心肌梗死或不稳定型心绞痛患者血清中IgE水平升高；它们几乎是稳定型心绞痛患者或无冠心病患者的两倍。IgE及其高亲和受体Fc¿R1在人动脉粥样硬化病变中高表达，定位于富含巨噬细胞（M¿）的区域，并共定位于病变平滑肌细胞（SMCs）和内皮细胞（ECs）。初步实验表明，在缺乏Fc¿R1¿-亚基的情况下，与Apoe-/-对照小鼠相比，易发生动脉粥样硬化的载脂蛋白e-缺陷（Apoe-/-）小鼠胸腹主动脉的脂质沉积减少了75%，主动脉弓的动脉粥样硬化病变大小减少了50%。体外细胞培养研究表明，IgE诱导M¿，SMC和EC丝裂原活化蛋白激酶（MAPK）途径的激活，同时增加炎症分子的产生和细胞凋亡。令人惊讶的是，IgE刺激了Fc R1链和toll样受体4 （TLR4）之间的复合物形成。Fc¿R1¿-亚基和TLR4都是ige诱导的M -细胞因子和趋化因子表达和细胞凋亡所必需的。此外，IgE在M¿上的这些活性与Na+-H+交换器NHE1的激活相关，随后是细胞外pH降低。这些新的初步发现与先前的观察结果一致，即在人类动脉粥样硬化病变中，凋亡细胞聚集在富含脂质的坏死核心周围，pH值（pH值7.15 ~ 0.01）明显低于相同病变的其他区域（pH值7.55 ~ 0.32，P=0.0001）。因此，我们假设IgE通过调节M¿、血管SMC和EC炎症和凋亡来促进动脉粥样硬化，而这些过程依赖于Fc¿R1和TLR4的相互作用以及NHE1的激活。我们提出两个具体目标来检验这一假设：1)。探讨IgE刺激M¿和血管SMC、EC炎症和凋亡的分子机制。2）. 研究IgE或IgE受体Fc¿R1的抑制或缺乏是否会减少动脉粥样硬化，并测试IgE介导的M¿激活在动脉粥样硬化中的重要性。我们期望在这两个目标中提出的实验将建立IgE在心肌和血管细胞病理生物学中的重要和新的作用，并直接参与动脉粥样硬化的发生。

DESCRIPTION (provided by applicant): Immunoglobulin E (IgE) associates with allergic responses, but we found that its serum levels are enhanced in patients with acute myocardial infarction or unstable angina pectoris; they are nearly double those in patients with stable angina pectoris or without coronary heart disease. Both IgE and its high-affinity receptor Fc¿R1 were expressed highly in human atherosclerotic lesions, localized to areas rich in macrophages (M¿), and colocalized to lesion smooth-muscle cells (SMCs) and endothelial cells (ECs). Preliminary experiments showed that in the absence of Fc¿R1 ¿-subunit, atherosclerosis-prone apolipoprotein E-deficient (Apoe-/-) mice developed 75% fewer lipid depositions in the thoracic-abdominal aorta and had a >50% reduction in atherosclerotic lesion sizes in the aortic arch, compared with Apoe-/- control mice. In vitro cell culture studies demonstrated that IgE induced activation of M¿, SMC, and EC mitogen-activated protein kinase (MAPK) pathway, along with enhanced inflammatory molecule production and apoptosis. Surprisingly, IgE stimulated a complex formation between Fc¿R1 ¿-chain and Toll-like receptor 4 (TLR4). Both Fc¿R1 ¿-subunit and TLR4 are necessary for IgE-induced M¿ cytokine and chemokine expression and apoptosis. Furthermore, these activities of IgE on M¿ associate with activation of Na+-H+ exchanger NHE1, followed by extracellular pH reduction. These novel preliminary findings are consistent with prior observations that in human atherosclerotic lesions, apoptotic cells cluster around lipid-rich necrotic cores, where the pH values are significantly lower (pH 7.15¿0.01) than in other areas of the same lesions (pH 7.55¿0.32, P=0.0001). Therefore, we hypothesize that IgE contributes to atherosclerosis by regulating M¿, vascular SMC, and EC inflammation and apoptosis, and that these processes depend on Fc¿R1 and TLR4 interaction as well as on NHE1 activation. We propose two specific aims to test this hypothesis: 1). To examine the molecular mechanisms by which IgE stimulates M¿ and vascular SMC and EC inflammation and apoptosis. 2). To examine whether inhibition or deficiency of IgE or IgE receptor Fc¿R1 reduces atherosclerosis, and to test the importance of IgE-mediated M¿ activation in atherogenesis. We anticipate that the experiments proposed in both aims will establish an important and novel role of IgE in M¿ and vascular cell pathobiology, and a direct participation of IgE in atherogenesis. PUBLIC HEALTH RELEVANCE: IgE is produced by plasma cells in response to allergic reactions. Recent discoveries of mast cell functions in atherosclerosis, and our preliminary studies of in vitro cell culture and in vivo mouse experimental atherosclerosis, prompted the hypothesis that IgE stimulates inflammatory cell and vascular cell inflammation and apoptosis, thereby promoting atherogenesis. These IgE activities are mediated by coordinate interactions between the IgE receptor Fc¿R1 and TLR4, and via activation of the Na+-H+ exchanger NHE1. Deficiency or pharmacological inactivation of Fc¿R1, TLR4, or NHE1 blocks IgE activities, and may thus reduce atherogenesis.