Role of ECM-associated IL-33 in Functional Remodeling After Myocardial Infarction

项目摘要/摘要 心肌梗死(MI)期间的缺血导致心肌细胞猝死，从而引发强烈的 炎症反应，但炎症阶段的及时消退是进入修复性阶段所必需的 分阶段进行，尽量减少疤痕。炎症期延长与不良脑室相关 可进展为临床心力衰竭的重塑反应。目前的治疗选择是有限的，而且未能 预防或逆转心肌梗死后免疫驱动的纤维化。拟议工作的主题是IL- 33主动调节免疫反应可最大限度地减少纤维化，保护心肌功能 缺血性损伤。由细胞外基质(Ecm)组成的生物支架被证明可以减少瘢痕形成。 在啮齿动物模型中，MI后，但其潜在的机制仅被部分了解。身份的鉴定 白细胞介素33(IL-33)稳定储存在细胞外基质中，提示其在细胞外基质介导的血管内皮细胞损伤中可能起重要作用。 免疫调节和建设性重塑反应。新出现的证据表明，IL-33支持组织 修复，特别是在心血管疾病模型中，通过其同源受体ST2发出信号。IL-33已经 以前被认为是核蛋白，但最近的研究发现IL-33稳定地整合到细胞外基质中 通过封装在基质结合的纳米微囊(MBV)中，在ECM降解到靶的过程中释放 渗入免疫细胞。我们发现含有IL-33的MBV可以引导巨噬细胞分化为 一种通过不涉及ST2受体的途径促进重塑的M2表型。身份的鉴定 MBV诱导的ST2非依赖性IL-33信号机制本身是新的，但在 心肌梗死的背景，因为可溶的、拮抗形式的ST2的表达水平是 心肌梗死后升高，与预后不良有关。假设ECM内的MBV IL-33是介导早期ST2非依赖性前重塑巨噬细胞所必需的重要来源 心肌缺血后的分化和直接构造性重构。拟议的研究将首先界定 巨噬细胞中受ST2非依赖性信号机制调控的基因谱系 探讨IL-33介导的免疫调节在预防免疫纤维化中的作用。结果是 这项工作可能使新的免疫调节方法，以保护缺血损伤后的心肌。

PROJECT SUMMARY/ABSTRACT Ischemia during myocardial infarction (MI) causes sudden cardiomyocyte death that initiates an intense inflammatory response, but timely resolution of the inflammatory phase is necessary to move into the reparative phase and minimize scarring. A prolonged pro-inflammatory phase is associated with an adverse ventricular remodeling response that can progress to clinical heart failure. Current therapeutic options are limited and fail to prevent or reverse immune-driven fibrosis after myocardial infarction. The theme of the proposed work is that IL- 33 driven modulation of the immune response can minimize fibrosis and preserve myocardial function after ischemic injury. Bioscaffolds composed of extracellular matrix (ECM) have been shown to minimize scarring after MI in rodent models, but the underlying mechanisms are only partially understood. The identification of interleukin-33 (IL-33) stably stored within the ECM suggests a potential role in the ECM-mediated immunomodulation and constructive remodeling response. Emerging evidence shows that IL-33 supports tissue repair, especially in models of cardiovascular disease, by signaling through its cognate receptor, ST2. IL-33 has previously been considered a nuclear protein, but recent studies have found IL-33 stably integrated into the ECM by encapsulation within matrix bound nanovesicles (MBV) that are released during ECM degradation to target infiltrating immune cells. We have found that MBV containing IL-33 can direct macrophage differentiation toward a pro-remodeling M2 phenotype through a pathway that does not involve the ST2 receptor. The identification of an ST2-independent IL-33 signaling mechanism induced by MBV is novel in itself but is particularly important in the context of myocardial infarction because expression levels of a soluble, antagonistic form of ST2 are increased following MI injury and associated with poor prognosis. It is hypothesized that MBV within the ECM are a critical source of IL-33 necessary to mediate early ST2-independent pro-remodeling macrophage differentiation and direct constructive remodeling after myocardial ischemia. The proposed studies will first define the repertoire of genes regulated by the ST2-independent signaling mechanism in macrophages and then investigate the role of IL-33 mediated immunomodulation in preventing immune-driven fibrosis. The results of this work my enable novel immunomodulatory approaches to protect the myocardium after ischemic injury.