Resolution of inflammation in atherosclerosis

解决动脉粥样硬化炎症

• 批准号: 233676545
• 负责人: Professor Dr. Oliver Söhnlein
• 金额: --
• 依托单位: Institut für Experimentelle Pathologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/233676545?language=en
• 关键词: Resolution; inflammation; atherosclerosis

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.

动脉粥样硬化是动脉壁的慢性炎症，是中风和心肌梗塞的潜在病理机制。我们最近发现，中性粒细胞在动脉粥样硬化的早期和晚期浸润大动脉，并且中性粒细胞减少症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（ROS）来指导炎症过程。然而，由于中性粒细胞是短命细胞，凋亡中性粒细胞的免疫调节特性在动脉粥样硬化中发挥着重要的调节机制。白细胞凋亡发生在动脉粥样硬化的所有阶段，其他研究人员将巨噬细胞作为凋亡细胞的来源。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，因此凋亡细胞会发生继发性坏死。在此，申请人假设除了巨噬细胞和平滑肌细胞之外，中性粒细胞也是动脉粥样硬化中凋亡细胞的主要来源，并且对中性粒细胞凋亡的信号通路、中性粒细胞清除机制以及刺激中性粒细胞清除时释放的分辨率信号进行特异性干扰将为治疗动脉粥样硬化开辟新的治疗途径。 人类和小鼠动脉粥样硬化不同阶段中性粒细胞凋亡的发生率。此后，申请人将使用过继转移策略和中性粒细胞凋亡率改变的小鼠来解决中性粒细胞凋亡对动脉粥样硬化的阶段依赖性贡献。最后，申请人将特异性干扰中性粒细胞凋亡和清除，以刺激早期斑块消退和后期斑块稳定。在早期阶段，中性粒细胞凋亡通过干扰刺激 Nf-KB 或抑制 ROS 的信号通路而增加。增强的中性粒细胞凋亡将刺激内源性解决机制，从而消退动脉粥样硬化。后期的干扰旨在减少持续的动脉白细胞浸润，刺激中性粒细胞清除和炎症过程的消退，最终促进斑块稳定。

项目成果

Annexin A1 counteracts chemokine-induced arterial myeloid cell recruitment.

• DOI: 10.1161/circresaha.116.305825
• 发表时间: 2015-02-27
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Drechsler M;de Jong R;Rossaint J;Viola JR;Leoni G;Wang JM;Grommes J;Hinkel R;Kupatt C;Weber C;Döring Y;Zarbock A;Soehnlein O
• 通讯作者: Soehnlein O

Resolving Lipid Mediators Maresin 1 and Resolvin D2 Prevent Atheroprogression in Mice.

• DOI: 10.1161/circresaha.116.309492
• 发表时间: 2016-08
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Joana R. Viola;Patricia Lemnitzer;Y. Jansen;G. Csaba;Carla Winter;Carlos Neideck;C. Silvestre-Roig;G. Dittmar;Y. Döring;Maik Drechsler;C. Weber;R. Zimmer;N. Cenac;O. Soehnlein