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: 10347378
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10347378
• 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; Lead; Lesion; Link; Logistics; Membrane; Mentors; Metabolic Pathway; Modeling; Mus; Myocardial Infarction; Necrosis; Nutrient; Ornithine Decarboxylase; Pathway interactions; Phagocytosis; Phagosomes; Phase; Process; Publishing; Putrescine; 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; macrophage; 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)是工业化世界的主要死亡原因。大多数动脉粥样硬化斑块在临床上是无症状的；然而，部分斑块可导致心肌梗死、中风或猝死。与临床事件相关的动脉粥样瘤的特征是大的坏死核，这是由于对凋亡细胞(ACS)的缺陷清除所致。当功能正常时，急性冠脉综合征的清除，也就是所谓的“胞吐”，可以消除炎症。因此，在晚期病变中增强胞吐作用可能会稳定易破裂的斑块，减少临床事件。虽然导致一种AC吞噬的机制已经很清楚，但在体内单个巨噬细胞(MΦS)必须吞噬许多AC，称为“持续吞噬”。因此，两个关键的悬而未决的问题是(A)MΦS如何处理因降解AC而产生的货物，以及(B)提示MΦS先前摄入AC以内化后续AC的机制是什么。 因此，本提案的总体目标是了解使急性冠脉综合征持续清除的信号和代谢途径，并利用这些途径制定新的治疗策略。这项提议测试了两条对持续泡泡细胞吞噬至关重要的新途径。在第一个途径中，MΦS通过精氨酸酶1和鸟氨酸脱羧酶的顺序作用，将AC衍生的精氨酸代谢成腐胺，从而重塑肌动蛋白细胞骨架。在第二条途径中，MΦS对AC来源的营养物质过量的反应是通过刺激 营养传感器mTORC1将囊泡回收到细胞表面，并为发育中的吞噬小体提供质膜。目的1探索AC衍生的精氨酸被代谢为腐胺的假说，并研究腐胺调节细胞骨架重塑的机制。目的2将验证这一假说，并探讨其中的机制，腐胺合成酶Arg1和ODC推动动脉粥样硬化消退和炎症消退。目的3探讨SLC38A9感应AC衍生的精氨酸和胆固醇以激活mTORC1的假设，并确定驱动第二个AC内化的机制。这些目标的成功实现将为MΦS如何感知和代谢摄入的急性冠脉综合征提供新的机制洞察力，这将为遏制心血管疾病提供新的治疗机会。