Novel mechanisms for the generation of resolving monocytes

产生解析单核细胞的新机制

• 批准号: 10586050
• 负责人: LIWU LI
• 金额: $ 39.1万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586050
• 关键词: Animal Model; Anti-Inflammatory Agents; Arterial Fatty Streak; Atherosclerosis; Biological Assay; Cells; Characteristics; Data; Development; Endotoxemia; Exhibits; Feedback; Flow Cytometry; Generations; Goals; Homeostasis; Human; Immunologic Memory; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Mediating; Mediator; Memory; Molecular; Molecular and Cellular Biology; Mus; Nature; Necrosis; Oxidation-Reduction; Pathogenesis; Play; Reporting; Resolution; Role; STAT1 gene; TLR4 gene; Testing; Training; Transfusion; genetic approach; in vivo; monocyte; new therapeutic target; novel; peroxisome; pharmacologic; prevent; recruit; single cell sequencing

PROJECT SUMMARY Low-grade inflammatory monocytes are increasingly recognized as key contributors for the pathogenesis of atherosclerosis through their enhanced recruitment and retention within the atherosclerotic plaques, as well as their compromised ability of cleaning up necrotic cell debris. However, mechanisms responsible for resolving monocyte inflammation are poorly understood, thus hindering translational efforts in resolving monocyte- mediated inflammatory polarization and the treatment of atherosclerosis. The PI recently reported that the training of low-grade inflammatory monocytes requires the critical cellular TLR4 adaptor molecule TRAM. Our data show that TRAM is uniquely responsible for the inflammatory polarization of monocytes, through a novel mechanism in disrupting pexophagy-mediated peroxisome homeostasis. Tram-/- monocytes have elevated PPAR and PEX5, enhanced pexophagy, reduced ROS, and reduced inflammatory polarization. Intriguingly, Tram-/- monocytes also express increased anti-inflammatory mediators (RvD1 and CD200R) characteristic of “resolving” monocytes, and can actively propagate resolution to neighboring monocytes through CD200R in vitro and in vivo. Tram-/- mice exhibit reduced development of atherosclerosis. Transfusion of Tram-/- resolving monocytes can reduce atherosclerosis pathogenesis. Based on these novel findings, the long term goal is to define novel therapeutic targets for sustaining monocyte homeostasis and preventing/treating atherosclerosis. The current objective is to define molecular and cellular mechanisms by which TRAM may serve as a key switch controlling the generation of either inflammatory or resolving monocytes relevant to the pathogenesis or treatment of atherosclerosis. The central hypothesis is that TRAM deletion will not only block the polarization of low-grade inflammatory monocytes, but also enable the generation and propagation of resolving monocytes conducive for the treatment of atherosclerosis, through enhancing peroxisome homeostasis. To test this hypothesis, the following integrated studies will be conducted. Aim 1 will test the hypothesis that the TRAM- PSMB10 circuitry drives the inflammatory polarization of low-grade inflammatory monocytes through disrupting pexophagy. Aim 2 will test the hypothesis that TRAM deletion and reduction of immunoproteasome PSMB10 enable the generation of anti-inflammatory resolving monocytes through sustained activation of PPAR /peroxisome homeostasis. Aim 3 will test the translational hypothesis that resolving monocytes with enhanced peroxisome homeostasis can propagate resolution memory and reduce the pathogenesis of atherosclerosis. Together, the proposed studies will advance the field of innate immune memory, by delineating the novel role of TRAM-circuitry in the training of “inflammatory” vs “resolving” monocytes, bearing translational relevance to the pathogenesis and treatment of atherosclerosis.

项目摘要 低度炎症单核细胞越来越多地被认为是导致的关键因素 动脉粥样硬化通过其在动脉粥样硬化斑块中的招募和保留率增强以及 他们清理坏死细胞碎片的能力受损。但是，负责解决的机制 单核细胞炎症的理解很少，从而阻碍了转化的努力来解决单核细胞 介导的炎症极化和动脉粥样硬化的治疗。 PI最近报告了 低度炎症单核细胞的训练需要关键的细胞TLR4适配器分子型Tram。我们的 数据表明，电车通过一种新颖的 破坏果皮介导的过氧化物体稳态的机制。电车 - / - 单核细胞升高 PPAR和PEX5，增强的PEXOPHAGY，ROS减少，炎症极化减少。有趣的是， 电车 - / - 单核细胞还表达增加的抗炎介质（RVD1和CD200R）的特征 “解决”单核细胞，并可以通过CD200R在体外积极地传播到相邻单核细胞的分辨率 和体内。电车 - / - 小鼠表现出减少动脉粥样硬化的发育。电车的输血 - / - 解决 单核细胞可以减少动脉粥样硬化的发病机理。根据这些新颖的发现，长期目标是 定义新的热靶标，用于维持单核细胞稳态和预防/治疗动脉粥样硬化。 当前的目的是定义电车可以用作钥匙开关的分子和细胞机制 控制与发病机理相关的炎症或解决单核细胞的产生 治疗动脉粥样硬化。中心假设是电车缺失不仅会阻止 低度炎症单核细胞，但也可以使单核细胞的产生和传播 通过增强过氧化物体稳态来治疗动脉粥样硬化的导电。测试这个 假设将进行以下综合研究。 AIM 1将检验以下假设。 PSMB10电路通过破坏低度炎症单核细胞的炎症极化 pexophagy。 AIM 2将检验以下假设，即导轨缺失和减少免疫蛋白酶体PSMB10 通过持续激活PPAR，可以生成抗炎分辨率的单核细胞 /过氧化物体稳态。 AIM 3将测试以增强的单核细胞解析的翻译假设 过氧体稳态可以传播分辨率记忆并减少动脉粥样硬化的发病机理。 拟议的研究一起将通过描述新的作用来推动先天免疫记忆的领域 在训练“炎症”与“解决”单核细胞的训练中 动脉粥样硬化的发病机理和治疗。