Resolution of Inflammation in healing Myocardial Infarcts

缓解心肌梗塞中的炎症

• 批准号: 8682984
• 负责人: Nikolaos G Frangogiannis
• 金额: $ 40.92万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8682984
• 关键词: Acute; Affect; Area; Biological; Biology; Cardiac; Cardiac Myocytes; Cells; Cicatrix; Complement; Containment; Defect; Development; Down-Regulation; Extracellular Matrix; Family; Fibroblasts; Functional disorder; Funding; Healed; Heart failure; Immune; Immune response; In Vitro; Infarction; Infiltration; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Injury; Interleukin 2 Receptor; Interleukin Receptor; Interleukin-1; Interleukin-1 Receptors; Interleukins; Knockout Mice; Laboratories; Leukocytes; MAP Kinase Gene; Mediating; Molecular; Myocardial Infarction; Myocardium; Necrosis; Pathogenesis; Pathway interactions; Phenotype; Phosphotransferases; Play; Process; Proteins; Reaction; Regulation; Repression; Resolution; Role; Signal Pathway; Signal Transduction; System; Testing; Time; Tissues; Toll-Like Receptor 1; Up-Regulation; base; cell type; chemokine; cytokine; gain of function; healing; in vivo; insight; macrophage; member; monocyte; novel; prevent; protective effect; public health relevance; receptor; repaired; research study; response; therapeutic target; tissue repair; wound

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.

描述（由应用提供）：心肌炎症触发强烈的炎症反应，可清除死细胞和基质碎片的梗塞。梗塞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，这些抑制性途径限制了保护梗塞心脏免受过量基质降解和不良重塑的炎症反应。负责控制和解决侵入后炎症的停止信号中的缺陷可能导致室内词典的强调，并有助于心力衰竭的发展。 Toll样受体（TLR）/白介素（IL）-1信号通路对于组织损伤后炎症器级联反应至关重要，但需要严格调节以防止过度活跃 免疫炎症反应。我们假设内源性抑制信号的激活对于心肌违规后TLR/IL-1反应的负调控是必要的，以防止不受控制的注射并限制扩张性重塑。我们将 探索两种新的新途径，负责抑制梗塞心肌中先天免疫反应：1）我们已经确定了肠间受体相关激酶（IRAK） - M的成员，IRAK-M家族的成员，缺乏激酶活性，是一个关键的细胞内信号，以防止内部的肌肉梗死和不良反应，并防止了肌肉反应过度，并在不反应的情况下上调。退化。 IRAK-M表达梗死巨噬细胞抑制其炎症活性。我们的实验表明，心脏成纤维细胞中的IRAK-M上调可能会限制其基质降解能力而不会影响其炎症潜力。这些效果可以通过IRAK-M和TGF-系统之间的新生物学相互作用来介导。 2）我们建议，动态，细胞类型特异性的1型IL-1受体（IL-1R1）和诱饵2受体（IL-1R2）的表达变化在调节炎症和恢复反应后可能起关键作用。 IL-1R1早期的单核细胞/巨噬细胞和心脏成纤维细胞中的上调可能诱发炎症作用，而IL-1R1的晚期下调以及诱导受体IL-1R2的诱导可能是终止心肌中终止IL-1信号的分子下调。这些概念将在三个特定目标中进行探讨：具体目的1：研究内源性IRAK-M上调作为限制TLR/IL-1驱动的注射的受保护机制的作用，以防止过度活跃的单核细胞/巨噬细胞反应并保护不良后输入后重塑。具体目标2：研究IRAK-M在调节成纤维细胞表型和控制心肌违规后基质重塑方面的作用，并剖析导致心脏成纤维细胞中IRAK-M作用的途径。具体目的3：研究细胞类型在信号传导和诱饵IL-1R表达中的特异性变化在心肌违规后调节炎症和修复中的作用。我们的研究将为心肌违规后不良重塑和心力衰竭的发病机理提供新的见解，并可能确定新的诺言是治疗靶标的。此外，IRAK-M对成纤维细胞功能的新作用及其与TGF-途径的潜在相互作用对组织注射和修复的生物学具有重要意义。