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

表达 TNFR1 的外泌体是心肌梗塞后脾脏病理性免疫激活的关键介质

基本信息

批准号：
10675087
负责人：
Shyam Sunder Bansal
金额：
$ 2.91万
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 2023-09-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10675087
关键词：
Adoptive Transfer Animal Model Antigen-Presenting Cells Antigens Biology Bone Marrow Breeding CD4 Positive T Lymphocytes Cardiac Cardiac Myocytes Cardiovascular system Cells Circulation Clinical Clinical Research Clonal Expansion Collaborations Communication 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 Incubated Infarction Infiltration Inflammation Inflammatory Injections Ischemia Knowledge Label Left Left Ventricular Remodeling Left ventricular structure Letters Ligation Lymphoid Lymphoid Tissue Macrophage Measures Mediating Mediator Membrane Messenger RNA MicroRNAs Mitochondrial Proteins Molecular Mus Muscle Cells Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Myocardium 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 T-Cell Activation T-Lymphocyte TNFRSF1A gene TNFRSF1B gene Testing Tissues Tumor Necrosis Factor Receptor Ventricular Vesicle cell type cellular targeting exosome experience healing heart function hematopoietic tissue immune activation immune modulating agents immunogenic immunoregulation intercellular communication intravenous administration intravenous injection ischemic injury monocyte preclinical study prevent response restraint 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.

项目摘要免疫激活是心肌梗塞（MI）的标志，并决定梗塞愈合并左心室（LV）重塑。它在临床前和临床研究中都建立了梗塞免疫后立即脾脏和骨ro（BM）出口到全身循环的细胞，并流向缺血性心。这表明受伤心脏的伤害信号传达给淋巴机，并造血组织启动心脏特异性免疫反应。但是，这些信号被转移到诸如脾之类的免疫壁细分市场中，尚不清楚。最近的研究表明，外泌体，30-100 nm尺寸的膜蔬菜是有效的可以将mRNA，miRNA和蛋白质的细胞间通信车辆用于遥远的时机生理和病理免疫激活。众所周知，循环的外泌体水平增加在心肌细胞损伤期间，并在其货物中含有肉类，胞质和线粒体蛋白。尽管这种理解，尚不清楚外泌体是否也用作造成损害的抗原载体 - 相关的蛋白质信号从缺血性心肌到脾脏，以进行免疫激活。确实，我们的初步结果清楚地表明缺血性心脏（与假）降低到幼稚的小鼠诱导I）收缩功能障碍（末端增加 - 舒张期和终端节量和提高的射血分数），ii）损伤的基因表达相关的损伤表达信号（S100A8，S100A9和eotaxin）在左腔中，iii）脾脏重塑，iv）先天浸润和心肌中的自适应免疫力。此外，MI外泌体表达肿瘤坏死因子受体1（TNFR1；而非TNFR2）在其膜上，这是一种经典的促炎信号分子，该分子是已显示与HF严重程度和心脏功能障碍相关。重要的是，静脉注射从1D MI TNFR1 - / - 小鼠中分离出的外泌体未能诱导幼稚的小鼠心脏功能障碍提示外泌体TNFR1在MI后介导免疫激活中的潜力，以前未知的作用和心脏功能障碍。因此，这导致我们假设外泌体携带心脏抗原进行介导 MI期间的脾脏免疫细胞激活对于免疫细胞介导的病理LV重塑至关重要，并且这些作用取决于外泌体TNFR1表达。重要的是，这些是关键的细胞靶标用于免疫调节。我们将通过i）确定sleen的病理生理作用来检验这一假设在MI之后介导外骨体处理时，ii）定义囊泡TNFR1在外泌体中的来源和作用介导的心脏功能障碍和iii）确定外泌体TNFR1在介导免疫原性中的作用信号。