Resolution of Inflammation in healing Myocardial Infarcts

描述（由申请人提供）：心肌梗死引发强烈的炎症反应，用于清除梗死区的死细胞和基质碎片。梗死心肌的最佳修复需要及时解决炎症和激活内源性抑制途径，抑制炎症反应，保护梗死心脏免受过度基质降解和不良重塑。负责抑制和缓解梗死后炎症的STOP信号的缺陷可能导致心室扩张加重，并导致心力衰竭的发展。 Toll样受体（TLR）/白细胞介素（IL）-1信号通路对于组织损伤后炎症级联反应的启动至关重要，但需要严格调控以防止过度活跃的炎症级联反应。 免疫炎症反应。我们假设内源性抑制信号的激活对于心肌梗死后TLR/IL-1反应的负调节是必要的，以防止不受控制的炎症和限制扩张性重塑。我们将 探索两种负责抑制梗死心肌先天免疫反应的新途径：1）我们已经鉴定出白细胞介素受体相关激酶（IRAK）-M，它是缺乏激酶活性的IRAK-M家族成员，是一种关键的细胞内信号，在心肌梗死后上调并保护梗死心脏免受不良重塑，抑制炎症并防止过度基质降解。梗死巨噬细胞中IRAK-M的表达抑制其炎症活性。我们的实验表明，心脏成纤维细胞中的IRAK-M上调可能限制其基质降解能力，而不影响其炎症潜力;这些作用可能通过IRAK-M和TGF-β系统之间的新型生物相互作用介导。 2)我们认为，动态的，细胞类型特异性变化的信号1型IL-1受体（IL-1 R1）和诱饵2型受体（IL-1 R2）的表达可能发挥至关重要的作用，在调节炎症和修复反应后梗死。单核细胞/巨噬细胞和心脏成纤维细胞中的早期IL-1 R1上调可诱导炎症反应，而IL-1 R1的晚期下调和诱饵受体IL-1 R2的诱导可作为终止梗死心肌中IL-1信号传导的分子汇。具体目标1：研究内源性IRAK-M上调作为抑制TLR/IL-1驱动的炎症、防止过度活跃的单核细胞/巨噬细胞应答和防止不利的梗死后重塑的保护机制的作用。 具体目标2：研究IRAK-M在心肌梗死后调节成纤维细胞表型和调节基质重塑中的作用，并分析心脏成纤维细胞中负责IRAK-M作用的途径。 具体目标3：目的：研究细胞类型特异性的信号转导和诱饵IL-1 R表达变化在心肌梗死后炎症调节和修复中的作用。 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，并可能确定新的有前途的治疗靶点。此外，IRAK-M对成纤维细胞功能的新作用及其与TGF-β通路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.