TNFR1 Expressing Exosomes are Critical Mediators of Pathological Immune Activation in the Spleen post-Myocardial Infarction

表达 TNFR1 的外泌体是心肌梗死后脾脏病理性免疫激活的关键介质

基本信息

批准号：
10483212
负责人：
Shyam Sunder Bansal
金额：
$ 55.24万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-07 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10483212
关键词：
Adoptive Transfer Animal Model Antigen-Presenting Cells Antigens Biology Blood Circulation Bone Marrow Breeding CD4 Positive T Lymphocytes Cardiac Cardiac Myocytes Cardiovascular system Cells Clinical Clinical Research Complex Congestive Heart Failure Data Dendritic Cells Disease Progression Distant Dyes EFRAC Echocardiography Eotaxin Fibrosis Functional disorder Gene Expression Heart Heart Injuries Heart failure Hypertrophy Hypoxia Immune Immune response Immunology Immunotherapeutic agent Incubated Infarction Infiltration Inflammation Inflammatory Injections Knowledge Label Left Left Ventricular Remodeling Left ventricular structure Letters Ligation Lymphoid Lymphoid Tissue Measures Mediating Mediator of activation protein Membrane Messenger RNA MicroRNAs Mitochondrial Proteins Molecular Mus Muscle Cells Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Myocardium Operative Surgical Procedures PKH 26 Pathologic Physiological Proteins Regulatory T-Lymphocyte Role S100A8 gene S100A9 gene Scientist Severities Signal Transduction Signaling Molecule Signaling Protein Source Spleen Splenocyte T memory cell TNFRSF1A gene Testing Tissues Tumor Necrosis Factor Receptor Ventricular Vesicle base cell type cellular targeting exosome experience healing heart function hematopoietic tissue immune activation immunogenic immunoregulation intercellular communication intravenous administration intravenous injection ischemic injury macrophage monocyte preclinical study prevent response tool trafficking wound healing

项目摘要

Project Summary Immune activation is a hallmark of myocardial infarction (MI) and dictate infarct healing and left ventricular (LV) remodeling. It is established, both in preclinical and clinical studies, that immediately after infarction immune cells from the spleen and the bone-marrow (BM) egress into the systemic circulation and traffic to the ischemic hearts. This suggests that the damage signals from the injured hearts are communicated to the lymphoid and the hematopoietic tissues to initiate cardiac-specific immune responses. However, the mechanisms by which these signals are transferred to the immune-rich niches such as the spleen are not known. Recent studies have shown that exosomes, membranous vesicles of 30-100 nm size, are potent intercellular communication vehicles that can shuttle mRNA, miRNA, and proteins to the distant tissues for physiological and pathological immune activation. It is also known that circulating exosomal levels increase during myocyte damage and contain sarcomeric, cytosolic and mitochondrial proteins in their cargo. Despite this understanding, it is not known if exosomes also serve as the antigenic vehicles to carry damage- associated protein signals from the ischemic myocardium to the spleen for subsequent immune activation. Indeed, our preliminary results clearly show that intravenous administration of exosomes released by the ischemic hearts (as compared to sham) into the naïve mice induce i) systolic dysfunction (increased end- diastolic and end-systolic volumes and decreased ejection fraction), ii) gene expression of damage associated signals (S100A8, S100A9 and eotaxin) in the left-ventricles, iii) splenic remodeling, and iv) infiltration of innate and adaptive immune cells in the myocardium. Moreover, MI exosomes expressed tumor necrosis factor receptor-1 (TNFR1; and not TNFR2) on their membranes, a classical pro-inflammatory signaling molecule that have been shown to correlate with HF severity and cardiac dysfunction clinically. Importantly, intravenous injection of exosomes isolated from 1d MI TNFR1-/- mice failed to induce cardiac dysfunction in naïve mice suggesting a potent, and previously unknown, role of exosomal TNFR1 in mediating immune activation post-MI and cardiac dysfunction. Therefore, this led us to hypothesize that exosomes carry cardiac antigens to mediate splenic immune cell activation during MI, are critical for immune cell mediated pathological LV remodeling, and these effects are dependent upon the exosomal TNFR1 expression. Importantly, these are key cellular targets for immunomodulation. We will test this hypothesis by i) determining the pathophysiological role of the spleen in mediating exosomal processing post-MI, ii) defining the source and role of vesicular TNFR1 in exosome mediated cardiac dysfunction, and iii) determining the role of exosomal TNFR1 in mediating immunogenic signaling.

项目概要免疫激活是心肌梗塞 (MI) 的标志，并决定梗塞愈合和左心室 (LV) 临床前和临床研究均表明，梗死后立即进行重塑。来自脾脏和骨髓 (BM) 的细胞进入体循环并运输到缺血区这表明来自受伤心脏的损伤信号被传递到淋巴和心脏。然而，造血组织启动心脏特异性免疫反应的机制。这些信号是否被转移到免疫丰富的微环境，例如脾脏，目前尚不清楚。最近的研究表明，外泌体（30-100 nm 大小的膜囊泡）具有有效的作用细胞间通讯载体，可以将 mRNA、miRNA 和蛋白质运送到远处组织还已知循环外泌体水平增加。尽管在心肌细胞损伤期间，它们的货物中含有肌节蛋白、胞质蛋白和线粒体蛋白。根据这一理解，目前尚不清楚外泌体是否也可以作为携带损伤的抗原载体—— 从缺血心肌到脾脏的相关蛋白质信号用于随后的免疫激活。事实上，我们的初步结果清楚地表明，静脉注射由将缺血性心脏（与假手术相比）注入幼稚小鼠中会诱导 i) 收缩功能障碍（终末期增加）舒张期和收缩末期容积以及射血分数降低），ii）相关损伤的基因表达左心室信号（S100A8、S100A9 和嗜酸细胞活化趋化因子），iii) 脾重塑，以及 iv) 先天性浸润此外，MI 外泌体表达肿瘤坏死因子。它们的膜上有受体-1（TNFR1；而不是 TNFR2），这是一种经典的促炎信号分子，临床上已证明与心力衰竭严重程度和心功能不全相关，重要的是静脉注射。注射从 1d MI TNFR1-/- 小鼠分离的外泌体未能诱导幼鼠心脏功能障碍表明外泌体 TNFR1 在介导 MI 后免疫激活中具有强大且先前未知的作用因此，这导致我们认为外泌体携带心脏抗原来介导。 MI 期间脾脏免疫细胞的激活对于免疫细胞介导的病理性左心室重塑至关重要，并且这些作用取决于外泌体 TNFR1 的表达，重要的是，这些是关键的细胞靶标。我们将通过 i) 确定脾脏的病理生理作用来检验这一假设。介导 MI 后外泌体加工，ii) 定义外泌体中囊泡 TNFR1 的来源和作用介导的心脏功能障碍，以及 iii) 确定外泌体 TNFR1 在介导免疫原性中的作用发信号。