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

项目总结/摘要 心肌梗死（MI）期间的缺血导致心肌细胞突然死亡， 炎症反应，但及时解决炎症阶段是必要的，以进入修复性 阶段和减少疤痕。长时间的促炎期与不良的心室收缩相关。 可能进展为临床心力衰竭的重塑反应。目前的治疗选择有限， 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驱动的免疫应答的调节可以使纤维化最小化并保护心肌功能。 缺血性损伤由细胞外基质（ECM）组成的生物支架已被证明可以最大限度地减少瘢痕形成 在啮齿类动物模型中，心肌梗死后，但其潜在机制仅部分了解。的识别 白细胞介素-33（IL-33）稳定储存在ECM内，表明在ECM介导的细胞凋亡中具有潜在作用。 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ST 2的信号传导。IL-33具有 以前被认为是一种核蛋白，但最近的研究发现IL-33稳定地整合到ECM中 通过包封在基质结合的纳米囊泡（MBV）内，所述纳米囊泡在ECM降解至靶细胞期间释放， 浸润免疫细胞我们已经发现含有IL-33的MBV可以指导巨噬细胞向 通过不涉及ST 2受体的途径促重塑M2表型。的识别 MBV诱导的ST 2非依赖性IL-33信号传导机制本身是新颖的，但在 心肌梗死的背景下，因为表达水平的可溶性，拮抗形式的ST 2是 MI损伤后增加，与预后不良相关。假设ECM内的MBV 是介导早期ST 2非依赖性促重塑巨噬细胞所必需的IL-33的关键来源 分化和心肌缺血后的直接结构性重构。拟议的研究将首先界定 巨噬细胞中由ST 2非依赖性信号机制调节的基因库， 研究IL-33介导的免疫调节在预防免疫驱动的纤维化中的作用。的结果 这一工作可能使新的免疫调节方法能够保护缺血性损伤后的心肌。

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.