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.

项目概要 低级炎症单核细胞越来越被认为是炎症发病机制的关键因素 通过增强动脉粥样硬化斑块内的募集和保留来预防动脉粥样硬化，以及 然而，它们清除坏死细胞碎片的能力受到损害。 人们对单核细胞炎症知之甚少，因此阻碍了解决单核细胞炎症的转化努力 介导的炎症极化和动脉粥样硬化的治疗。 低级炎症单核细胞的训练需要关键的细胞 TLR4 接头分子 TRAM。 数据表明，TRAM 通过一种新颖的方式对单核细胞的炎症极化负有独特的责任 破坏 pexophagy 介导的过氧化物酶体稳态的机制已升高。 PPAR 和 PEX5，增强自噬，减少 ROS，并减少炎症极化。 Tram-/- 单核细胞还表达增加的抗炎介质（RvD1 和 CD200R） “解析”单核细胞，并能在体外通过 CD200R 主动将解析传播到邻近的单核细胞 在体内，Tram-/- 小鼠表现出动脉粥样硬化的减少。 基于这些新发现，单核细胞可以减少动脉粥样硬化的发病机制。 确定维持单核细胞稳态和预防/治疗动脉粥样硬化的新治疗靶点。 目前的目标是定义 TRAM 作为关键开关的分子和细胞机制 控制与发病机制相关的炎症或消退单核细胞的产生，或 治疗动脉粥样硬化的中心假设是，TRAM 缺失不仅会阻止动脉粥样硬化的极化。 低级炎症单核细胞，但也能够产生和增殖溶解单核细胞 有利于动脉粥样硬化的治疗，通过增强过氧化物酶体稳态来检验这一点。 假设，将进行以下综合研究，目标 1 将检验 TRAM- 的假设。 PSMB10 电路通过破坏低级炎症单核细胞的炎症极化来驱动 目标 2 将检验 TRAM 缺失和免疫蛋白酶体 PSMB10 减少的假设。 通过持续激活 PPAR 能够产生抗炎解决单核细胞 /过氧化物酶体稳态。目标 3 将检验以增强的方式解决单核细胞的翻译假设。 过氧化物酶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制。 总之，拟议的研究将通过描述先天免疫记忆的新作用来推进先天免疫记忆领域的发展。 “炎症”与“消退”单核细胞训练中的 TRAM 电路，与转化相关 动脉粥样硬化的发病机制和治疗。