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

• 批准号: 10298774
• 负责人: Shyam Sunder Bansal
• 金额: $ 55.88万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/10298774
• 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

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 免疫激活是心肌梗死(MI)的一个标志，并决定着心肌梗死的愈合和左心室(LV) 改建。在临床前和临床研究中都证实，在脑梗塞后立即免疫 来自脾和骨髓(BM)的细胞进入体循环并输送到缺血区 红心。这表明，来自受伤心脏的损伤信号被传递到淋巴组织和 造血组织启动心脏特异性免疫反应。然而，通过这些机制 这些信号被传递到免疫丰富的区域，如脾。 最近的研究表明，外切体，即大小为30-100 nm的膜性囊泡，是有效的 一种细胞间通讯载体，可以将mrna、miRNA和蛋白质运送到远处的组织中 生理和病理免疫激活。我们还知道循环中的胞外体水平增加 在心肌细胞损伤过程中，它们的货物中含有肌节蛋白、胞浆蛋白和线粒体蛋白。尽管 这种理解，目前尚不清楚外切体是否也是携带损伤的抗原载体- 从缺血心肌到脾的相关蛋白信号，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 缺血心脏(与假手术相比)进入幼稚小鼠可引起：1)收缩功能障碍(末期心肌收缩功能增加)。 舒张期和收缩末期容量和射血分数降低)，II)相关损伤的基因表达 左心室的信号(S100A8、S100A9和嗜酸性粒细胞趋化因子)，iii)脾重塑，iv)先天的浸润 和心肌中的适应性免疫细胞。此外，MI外切体表达肿瘤坏死因子 受体-1(TNFR1；而不是TNFR2)，一种经典的促炎信号分子， 在临床上已被证明与心衰严重程度和心功能不全相关。重要的是，静脉注射 注射1D MI TNFR1-/-小鼠外切体不能引起幼稚小鼠心功能障碍 提示胞外体TNFR1在心肌梗死后介导免疫激活中具有先前未知的有效作用 和心脏功能不全。因此，这导致我们假设外切体携带心脏抗原进行中介。 急性心肌梗死时脾免疫细胞的激活，对免疫细胞介导的病理性左室重构至关重要。 这些作用依赖于外体TNFR1的表达。重要的是，这些都是关键的细胞目标 用于免疫调节。我们将通过确定脾的病理生理作用来检验这一假说。 在介导心肌梗塞后胞外体加工中，II)确定囊泡型TNFR1在胞外体中的来源和作用 介导的心功能障碍，以及iii)确定外体TNFR1在介导免疫原性中的作用 发信号。