Antiatherogenic effects of neutrophil alpha defensins

中性粒细胞α防御素的抗动脉粥样硬化作用

• 批准号: 8360808
• 负责人: KHALIL BDEIR
• 金额: $ 24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-05 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360808
• 关键词: Adhesions; Air; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Attenuated; Binding; Breeding; Cardiovascular Diseases; Cause of Death; Cells; Chronic; Crossbreeding; Data; Development; Diet; Disease; Endothelial Cells; Fatty acid glycerol esters; Foam Cells; Heterogeneity; Human; Immune; Immune response; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Lesion; Leukocytes; Lipoprotein (a); Lipoproteins; Longevity; Low-Density Lipoproteins; Measures; Mediating; Modeling; Mus; NF-kappa B; Neutrophil Activation; Pathway interactions; Peptides; Phenotype; Plasma; Play; Proteins; Reporting; Role; Signal Pathway; Sum; Testing; Transgenic Mice; alpha-Defensins; atherogenesis; atheroprotective; base; chemokine; cytokine; in vivo; insight; macrophage; monocyte; mortality; mouse model; neutrophil; novel; peptidomimetics; vascular inflammation

DESCRIPTION (provided by applicant): Atherosclerosis is a chronic inflammatory disease and is a leading cause of mortality in cardiovascular diseases. Recent studies demonstrate that monocytes and macrophage heterogeneity contribute to atherogenic and atheroprotective axes. This proposal focuses on the role that alpha-defensin (¿-def), a major protein expressed in human polymorphonuclear neutrophils (PMNs), plays in the immune response and genesis of atherosclerosis, a role that has been ignored in existing murine models of atherosclerosis because mice do express ¿-def, and in humans due to the short lifespan of PMNs in the plaque. We have shown that ¿-def is abundant in human plaques indicative of PMNs activation. To study the contribution of ¿-def to chronic inflammation and development of atherogenesis in vivo, we generated novel mice that express human ¿-def in their PMNs bred onto ApoE-/- (D+/+ApoE-/-). In preliminary studies D+/+ApoE-/- mice showed less atherosclerosis and reduced systemic inflammation compared with D-/-ApoE-/- control mice on a high fat diet. This is in line with recent studies that contrast with the widely accepted pro-inflammatory role of ¿-def, documented anti-inflammatory effects on macrophages and monocytes. Moreover, ¿-def inhibits activation of NF-kB in macrophages, inhibits adhesion of human and mouse macrophages to matrix proteins and increases the number of the regulatory resident subset of monocytes in inflammation mouse model. Together, these data support an anti-inflammatory, anti-atherogenic role for ¿-def in vivo. We hypothesized that ¿-def released from activated PMNs in nascent atherosclerotic lesions modulate the monocytes/macrophage subset distribution from a pro-inflammatory to an anti-inflammatory phenotype by inhibiting NF-kB activation and the subsequent expression of multi pro-inflammatory cytokines. To test this hypothesis, we will study the effect of ¿-def on atherosclerosis and inflammation in vivo and elucidate its mechanism of action both in vivo and on monocytes and macrophages using isolated ¿-def and neutrophils packed ¿-def in novel def+/+ mice that we developed. In sum, this proposal is a critical initial step to understand the critical role that ¿-def plays in inflammatio, and will provide a paradigm-shifting from, the widely accepted proinflammatory role of ¿-def, into immune modulator or anti-inflammatory role under conditions of chronic inflammation in atherosclerosis. PUBLIC HEALTH RELEVANCE: This proposal focuses on the role that alpha-defensin, a major protein expressed in human but not mice neutrophils, plays in the immune response and genesis of atherosclerosis. We will use a novel transgenic mouse to elucidate the pathways by which these peptides modulate the immune response in atherosclerosis.

描述（由申请人提供）：动脉粥样硬化是一种慢性炎症性疾病，是心血管疾病死亡的主要原因。最近的研究表明，单核细胞和巨噬细胞的异质性有助于动脉粥样硬化和动脉粥样硬化保护轴。该提案集中于α-防御素（<$-def），一种在人类多形核中性粒细胞（PMNs）中表达的主要蛋白质，在免疫应答和动脉粥样硬化发生中发挥的作用，在现有的动脉粥样硬化小鼠模型中，由于小鼠确实表达<$-def，以及在人类中，由于斑块中PMNs的寿命短，该作用被忽略。我们已经表明，<$-def是丰富的人类斑块指示中性粒细胞活化。为了研究<$-def对体内慢性炎症和动脉粥样硬化形成的贡献，我们产生了在ApoE-/-（D+/+ApoE-/-）上繁殖的PMN中表达人<$-def的新小鼠。在初步研究中，与高脂肪饮食的D-/-ApoE-/-对照小鼠相比，D+/+ ApoE-/-小鼠显示出较少的动脉粥样硬化和减少的全身炎症。这与最近的研究一致，该研究与广泛接受的<$-def的促炎作用形成对比，记录了对巨噬细胞和单核细胞的抗炎作用。此外，-def抑制巨噬细胞中NF-κ B的活化，抑制人和小鼠巨噬细胞与基质蛋白的粘附，并增加炎症小鼠模型中单核细胞的调节性驻留亚群的数量。总之，这些数据支持<$-def在体内的抗炎、抗动脉粥样硬化作用。我们假设，从新生动脉粥样硬化病变中活化的PMN释放的-def通过抑制NF-κ B活化和随后的多种促炎细胞因子的表达来调节单核细胞/巨噬细胞亚群分布，使其从促炎表型变为抗炎表型。为了验证这一假设，我们将研究<$-def在体内对动脉粥样硬化和炎症的作用，并在我们开发的新型def+/+小鼠中使用分离的<$-def和中性粒细胞包装的<$-def阐明其在体内和对单核细胞和巨噬细胞的作用机制。总之，该提议是理解<$-def在炎症中发挥的关键作用的关键初始步骤，并将提供从广泛接受的<$-def的促炎作用到动脉粥样硬化慢性炎症条件下的免疫调节剂或抗炎作用的范式转变。 公共卫生关系：该建议的重点是α-防御素，在人类而不是小鼠中性粒细胞中表达的主要蛋白质，在免疫反应和动脉粥样硬化的发生中发挥的作用。我们将使用一种新的转基因小鼠来阐明这些肽调节动脉粥样硬化免疫反应的途径。