Processing of Apoptotic Cell-Derived Cargo by Macrophages Continues Efferocytosis and Drives Atherosclerosis Regression

巨噬细胞对凋亡细胞衍生货物的加工继续胞吞作用并驱动动脉粥样硬化消退

• 批准号: 10581597
• 负责人: Arif Yurdagul
• 金额: $ 24.9万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581597
• 关键词: Actins; Affect; Apoptotic; Area; Arginine; Arterial Fatty Streak; Atherosclerosis; Award; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell membrane; Cell surface; Cells; Cellular Metabolic Process; Cholesterol; Clinical; Critical Pathways; Cues; Cytoskeleton; Data; Enzymes; Event; Funding; Future; Goals; Individual; Industrialization; Inflammation; Ingestion; Interleukin-10; Lesion; Link; Macrophage; Membrane; Mentors; Metabolic Pathway; Modeling; Mus; Myocardial Infarction; Necrosis; Nutrient; Ornithine Decarboxylase; Pathway interactions; Phagocytosis; Phagosomes; Phase; Process; Publishing; Putrescine; Recycling; Research; Resolution; Role; Rupture; Signal Pathway; Stroke; Sudden Death; Testing; Vesicle; Work; arginase; clinically relevant; collaborative environment; cytokine; detection of nutrient; in vivo; insight; lipid mediator; nanoparticle; novel; novel strategies; novel therapeutics; programs; sensor; trafficking; transcriptome sequencing; treatment strategy

Atherosclerotic cardiovascular disease (CVD) is the leading cause of death in the industrialized world. Most atherosclerotic plaques are clinically silent; however, a subset can lead to myocardial infarction, stroke, or sudden death. Atheromas that are linked to clinical events are characterized by large necrotic cores, which result from the defective clearance of apoptotic cells (ACs). When functioning normally, clearance of ACs, termed “efferocytosis”, resolves inflammation. Therefore, enhancing efferocytosis in advanced lesions may stabilize rupture-prone plaques and reduce clinical events. While the mechanisms that lead to phagocytosis of one AC have been well-defined, individual macrophages (MΦs) must engulf many ACs, termed “continued efferocytosis”, in vivo. Accordingly, two critical, unanswered questions are (a) how do MΦs process the cargo derived from degrading an AC, and (b) what mechanisms are in place that cue MΦs that have previously ingested an AC to internalize a subsequent AC. Therefore, the overall objective of this proposal is to understand the signaling and metabolic pathways that enable the continued clearance of ACs and to harness these pathways towards a novel treatment strategy. This proposal tests two new pathways critical for continued efferocytosis. In the first pathway, MΦs metabolize AC-derived arginine into putrescine, through the sequential action of arginase 1 (Arg1) and ornithine decarboxylase (ODC), to remodel the actin cytoskeleton. In the second pathway, MΦs respond to the overabundance of AC-derived nutrients by stimulating the nutrient sensor mTORC1 to recycle vesicles to the cell surface and supply the developing phagosome with plasma membrane. Aim 1 will explore the hypothesis that AC-derived arginine is metabolized into putrescine and examine the mechanisms by which putrescine regulates cytoskeletal remodeling. Aim 2 will test the hypothesis and investigate the mechanisms therein, that the putrescine-synthesizing enzymes Arg1 and ODC drive atherosclerosis regression and inflammation resolution. Aim 3 will explore the hypothesis that SLC38A9 senses AC-derived arginine and cholesterol to activate mTORC1 and identify the mechanisms that drive the internalization of a second AC. Successful completion of these aims will provide new mechanistic insight in how MΦs sense and metabolize the cargo from ingested ACs, which will provide new therapeutic opportunities to curb cardiovascular disease.

动脉粥样硬化性心血管疾病（CVD）是工业化国家的主要死亡原因。大多数动脉粥样硬化斑块在临床上是无症状的;然而，一个子集可导致心肌梗死、中风或猝死。与临床事件相关的动脉粥样硬化的特征在于大的坏死核心，其由凋亡细胞（AC）的缺陷清除引起。当功能正常时，AC的清除，称为“细胞增多症”，解决炎症。因此，在晚期病变中增强红细胞增多可能稳定破裂倾向的斑块并减少临床事件。虽然导致吞噬一个AC的机制已经被很好地定义，但个体巨噬细胞（MΦ）必须在体内吞噬许多AC，称为“持续吞噬作用”。因此，两个关键的未回答的问题是（a）MΦ如何处理来源于降解AC的货物，和（B）什么机制处于适当位置，提示先前摄取AC的MΦ内化随后的AC。 因此，本提案的总体目标是了解能够持续清除AC的信号传导和代谢途径，并将这些途径用于新的治疗策略。这项提议测试了两个新的途径，这两个途径对持续的红细胞增多至关重要。在第一条途径中，MΦ通过精氨酸酶1（Arg 1）和鸟氨酸脱羧酶（ODC）的顺序作用将AC衍生的精氨酸代谢成腐胺，以重塑肌动蛋白细胞骨架。在第二条途径中，MΦ通过刺激细胞内的细胞因子来响应过量的AC来源的营养素。 营养传感器mTORC 1将囊泡回收到细胞表面，并为发育中的吞噬体提供质膜。目的1将探讨AC衍生的精氨酸代谢为腐胺的假设，并研究腐胺调节细胞骨架重塑的机制。目的2将验证这一假设并研究其中的机制，即腐胺合成酶Arg 1和ODC驱动动脉粥样硬化消退和炎症消退。目的3将探索SLC 38 A9感知AC衍生的精氨酸和胆固醇以激活mTORC 1的假设，并确定驱动第二AC内化的机制。这些目标的成功完成将为MΦ如何感知和代谢来自摄入的AC的货物提供新的机制见解，这将为遏制心血管疾病提供新的治疗机会。

项目成果

Allosteric MAPKAPK2 inhibitors improve plaque stability in advanced atherosclerosis.

• DOI: 10.1371/journal.pone.0246600
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Ozcan L;Kasikara C;Yurdagul A Jr;Kuriakose G;Hubbard B;Serrano-Wu MH;Tabas I
• 通讯作者: Tabas I

Crosstalk Between Macrophages and Vascular Smooth Muscle Cells in Atherosclerotic Plaque Stability.

动脉粥样硬化斑块稳定性中巨噬细胞和血管平滑肌细胞之间的串扰。

• DOI: 10.1161/atvbaha.121.316233
• 发表时间: 2022-04
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Yurdagul A Jr

Assessing Efferocytosis in Atherosclerotic Lesions In Situ.

评估原位动脉粥样硬化病变中的胞吞作用。

• DOI: 10.1007/978-1-0716-1924-7_34
• 发表时间: 2022
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: YurdagulJr,Arif

Synthesis of siRNA nanoparticles to silence plaque-destabilizing gene in atherosclerotic lesional macrophages.

• DOI: 10.1038/s41596-021-00665-4
• 发表时间: 2022-03
• 期刊: NATURE PROTOCOLS
• 影响因子: 14.8
• 作者: Huang, Xiangang;Liu, Chuang;Kong, Na;Xiao, Yufen;Yurdagul, Arif, Jr.;Tabas, Ira;Tao, Wei
• 通讯作者: Tao, Wei

Dual-Fluorescence In Vitro Efferocytosis Assay.

双荧光体外胞吞作用测定。

• DOI: 10.1007/978-1-0716-1924-7_18
• 发表时间: 2022
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: YurdagulJr,Arif