Resolution of Inflammation in healing Myocardial Infarcts

描述(申请人提供)：心肌梗死会引发强烈的炎症反应，以清除心肌梗死中的死细胞和基质碎片。心肌梗死的最佳修复需要及时消除炎症反应，激活抑制炎症反应的内源性抑制通路，保护心肌免受基质过度降解和不良重构的影响。负责抑制和消退梗死后炎症的停止信号的缺陷可能会导致心腔扩张加剧，并导致心力衰竭的发展。Toll样受体(TLR)/白介素1(IL)-1信号通路对于组织损伤后炎症反应的启动至关重要，但需要严格调控，以防止过度活跃 免疫炎症反应。我们假设，激活内源性抑制信号对于心肌梗死后TLR/IL-1反应的负性调节是必要的，以防止失控的炎症和限制扩张性重塑。我们会 探索两条新的途径来抑制心肌梗死后的天然免疫反应：1)我们已经发现，白细胞介素型受体相关激酶(IRAK)-M是IRAK-M家族的一员，它缺乏激酶活性，是一个关键的细胞内信号，在心肌梗死后上调，保护梗塞心脏免受不利重构的影响，抑制炎症反应，防止过度的基质降解。梗死区巨噬细胞表达IRAK-M抑制其炎症活动。我们的实验表明，IRAK-M在心脏成纤维细胞中的上调可能限制其降解基质的能力，而不影响其炎症潜能；这些影响可能是通过IRAK-M和转化生长因子-β系统之间的新的生物相互作用来介导的。2)我们认为，信号转导的1型IL-1受体(IL-1R1)和诱饵2型受体(IL-1R2)表达的动态、细胞类型特异性的变化可能在脑梗塞后的炎症和修复反应的调节中发挥重要作用。IL-1R1在单核/巨噬细胞和心脏成纤维细胞中的早期上调可能诱导炎症反应，而IL-1R1的晚期下调和诱骗受体IL-1R2的诱导可能作为一个分子汇终止梗死心肌中的IL-1信号转导。这些概念将在三个特定目标中进行探讨：特定目标1：研究内源性IRAK-M上调作为一种保护机制的作用，以抑制TLR/IL-1驱动的炎症，防止过度活跃的单核/巨噬细胞反应，并防止不利的梗死后重塑。具体目的2：研究IRAK-M在心肌梗死后调控成纤维细胞表型和基质重塑中的作用，并探讨IRAK-M在心肌成纤维细胞中的作用途径。具体目的3：研究心肌梗死后细胞类型特异性信号转导和诱骗IL-1RS表达变化在炎症和修复中的作用。我们的研究将为心肌梗死后不良重构和心力衰竭的发病机制提供新的见解，并可能确定新的有希望的治疗靶点。此外，IRAK-M对成纤维细胞功能的新作用及其与转化生长因子-β途径的潜在相互作用在组织炎症和修复的生物学中具有重要意义。

DESCRIPTION (provided by applicant): Myocardial infarction triggers an intense inflammatory reaction that serves to clear the infarct from dead cells and matrix debris. Optimal repair of the infarcted myocardium requires timely resolution of inflammation and activation of endogenous inhibitory pathways that restrain the inflammatory response protecting the infarcted heart from excessive matrix degradation and adverse remodeling. Defects in the STOP signals responsible for containment and resolution of post-infarction inflammation may result in accentuated chamber dilation and contribute to the development of heart failure. Toll-Like Receptor (TLR)/Interleukin (IL)-1 signaling pathways are critical for initiation of the inflammator cascade following tissue injury, but need to be tightly regulated in order to prevent an overactive immunoinflammatory response. We hypothesized that activation of endogenous inhibitory signals is necessary for negative regulation of the TLR/IL-1 response following myocardial infarction, in order to prevent uncontrolled inflammation and to limit dilative remodeling. We will explore two novel pathways responsible for inhibition of the innate immune response in the infarcted myocardium: 1) We have identified Interleukin Receptor Associated Kinase (IRAK)-M, a member of the IRAK-M family that lacks kinase activity, as a key intracellular signal that is upregulated following myocardial infarction and protects the infarcted heart from adverse remodeling restraining inflammation and preventing excessive matrix degradation. IRAK-M expression in infarct macrophages inhibits their inflammatory activity. Our experiments suggest that IRAK-M upregulation in cardiac fibroblasts may limit their matrix-degrading capacity without affecting their inflammatory potential; these effects may be mediated through novel biological interactions between IRAK-M and the TGF-¿ system. 2) We suggest that dynamic, cell type-specific changes in expression of the signaling type 1 IL-1 receptor (IL-1R1) and of the decoy type 2 receptor (IL-1R2) may play a crucial role in regulation of the inflammatory and reparative response following infarction. Early IL-1R1 upregulation in monocytes/macrophages and in cardiac fibroblasts may induce inflammatory actions, whereas late downregulation of IL-1R1 and induction of the decoy receptor IL-1R2 may serve as a molecular sink terminating IL-1 signaling in the in infarcted myocardium. These concepts will be explored in three specific aims: Specific aim 1: to study the role of endogenous IRAK-M upregulation as a protective mechanism that restrains TLR/IL-1-driven inflammation, preventing hyperactive monocyte/macrophage responses and protecting from adverse post- infarction remodeling. Specific aim 2: to study the role of IRAK-M in modulating fibroblast phenotype and in regulating matrix remodeling following myocardial infarction and to dissect the pathways responsible for IRAK-M actions in cardiac fibroblasts. Specific aim 3: To study the role of cell-type specific changes in expression of signaling and decoy IL-1Rs in regulation of inflammation and repair following myocardial infarction. Our studies will provide new insights into the pathogenesis of adverse remodeling and heart failure following myocardial infarction and may identify new promising therapeutic targets. In addition, the novel effects of IRAK-M on fibroblast function and its potential interactions with the TGF- ¿ pathway have important implications in the biology of tissue inflammation and repair.