Resolution of inflammation in atherosclerosis

动脉粥样硬化是动脉壁的一种慢性炎症，是中风和心肌梗死的潜在病理机制。我们最近发现，在动脉粥样硬化的早期和晚期，中性粒细胞会渗入大动脉，而且中性粒细胞减少会缩小动脉粥样硬化病变的大小。从机制上讲，中性粒细胞通过释放预先形成的颗粒蛋白或活性氧物种(ROS)来指导炎症过程。然而，由于中性粒细胞是短暂的细胞，凋亡的中性粒细胞的免疫调节特性在动脉粥样硬化中是重要的调节机制。白细胞凋亡发生在动脉粥样硬化的所有阶段，其他研究人员将重点放在巨噬细胞作为凋亡细胞的来源上。虽然动脉粥样硬化早期的细胞凋亡被认为是有益的，但在后期它是致命的，因为凋亡细胞清除机制受损，因此凋亡细胞经历继发性坏死。在此，申请人假设，除了巨噬细胞和平滑肌细胞外，中性粒细胞是动脉粥样硬化中凋亡细胞的主要来源，对中性粒细胞凋亡信号通路的特异性干扰、中性粒细胞清除机制以及中性粒细胞清除后释放的分解信号的刺激将为动脉粥样硬化的治疗开辟新的途径。在这项提议中，申请人计划绘制人和小鼠动脉粥样硬化不同阶段中性粒细胞凋亡的发生率图。此后，申请者将使用过继转移策略和中性粒细胞凋亡率改变的小鼠解决中性粒细胞凋亡在动脉粥样硬化中的阶段依赖性贡献。最后，申请者将专门干扰中性粒细胞的凋亡和清除，以在早期阶段刺激斑块消退，在后期阶段促进斑块稳定。在早期阶段，通过干扰刺激核因子-KB或抑制ROS的信号通路，增加中性粒细胞的凋亡。增强的中性粒细胞凋亡将刺激内源性的分解机制，从而使动脉粥样硬化消退。后期干预的目的是减少持续的动脉白细胞渗透，刺激中性粒细胞清除和消退炎症过程，最终促进斑块稳定。

Atherosclerosis, a chronic inflammation of the arterial wall, is the underlying pathomechanism for stroke and myocardial infarction. We have recently shown that neutrophils infiltrate large arteries during early and late stages of atherosclerosis and that neutropenia reduces sizes of atherosclerotic lesions. Mechanistically, neutrophils instruct inflammatory processes through release of pre-formed granule proteins or reactive oxygen species (ROS). However, as neutrophils are short-lived cells, immune-modulatory properties of apoptotic neutrophils stand out as important regulatory mechanisms in atherosclerosis. Leukocyte apoptosis occurs throughout all stages of atherosclerosis and other investigators have focused on macrophages as the source of apoptotic cells. While apoptosis in early stages of atherosclerosis is considered beneficial, it is fatal at later stages as mechanisms of apoptotic cell clearance are impaired and hence apoptotic cells undergo secondary necrosis. Here, the applicant hypothesizes that besides macrophages and smooth muscle cells neutrophils are a major source of apoptotic cells in atherosclerosis and specific interference with signaling pathways of neutrophil apoptosis, mechanisms of neutrophil clearance, and stimulation of resolution signals released upon neutrophil clearance will open new therapeutic avenues for treatment of atherosclerosis.In this proposal the applicant plans to map the prevalence of neutrophil apoptosis at various stages of human and murine atherosclerosis. Thereafter, the applicant will address the stage-dependent contribution of neutrophil apoptosis to atherosclerosis using adoptive transfer strategies and mice with altered neutrophil apoptosis rates. Finally, the applicant will specifically interfere with neutrophil apoptosis and clearance to stimulate plaque regression at early stages and plaque stabilization at later stages. During early stages, neutrophil apoptosis is increased through interference with signaling pathways that stimulate Nf-KB or inhibit ROS. Enhanced neutrophil apoptosis shall stimulate endogenous resolution mechanisms and therewith regression of atherosclerosis. Interference at later stages is designed to reduce continued arterial leukocyte infiltration, stimulate neutrophil clearance and resolution of inflammatory processes ultimately promoting plaque stabilization.