MIF inhibition preserves cardiac function after myocardial ischemia and reperfusion by controlling the monocyte-differentiation and macrophage-polarization

MIF 抑制通过控制单核细胞分化和巨噬细胞极化来保护心肌缺血和再灌注后的心脏功能

基本信息

批准号：
390971602
负责人：
Professor Dr. Peter Lüdike
金额：
--
依托单位：
Klinik für Kardiologie und Angiologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/390971602?language=en
关键词：
MIF inhibition preserves cardiac function

项目摘要

Ischemic heart failure (HF) as a consequence of ischemic heart disease is the leading cause of death in the western world. After myocardial ischemia and reperfusion (I/R), activation of innate immune responses is an essential component to limit the extent of cardiac injury and facilitate healing. Recruitment of neutrophils and monocytes to the myocardium denotes the first step of healing, followed by monocyte differentiation into macrophages. Healing requires further a fine-tuned polarization of macrophages into reparative and inflammatory species. The mechanisms controlling monocyte differentiation and macrophage polarization in myocardial I/R are poorly understood yet. Damage-associated molecular patterns (DAMPs) are released from the ischemic myocardium during I/R and have recently emerged as key players in orchestrating this inflammatory response after acute myocardial infarction (AMI). DAMPs are recognized by pattern recognition receptors such as Toll-like receptor 4 (TLR4), which trigger inflammatory signaling cascades. Macrophage migration inhibitory factor (MIF) is a chemokine-like function (CLF) chemokine, an emerging class of molecules that functionally overlaps with the mediator classes of alarmins and DAMPs. MIF controls TLR4 expression in leukemia macrophages and is also released during myocardial I/R and exhibits auto- and intracrine cardioprotective activities. Own studies recently demonstrated that cardioprotection by MIF is prominent in the early phase of reperfusion and the applicant identified S-nitrosation as a novel posttranslational modification of MIF (SNO-MIF), which potentiates the cardioprotective properties of MIF while also regulating its secretion from cardiac tissue during reperfusion. Whether SNO-MIF has altered chemotactic properties and whether it affects monocyte differentiation and macrophage polarization in the heart during I/R stress is unknown. Here, the applicant aims to investigate whether MIF is a regulator of the DAMPs-associated immune response during myocardial I/R and whether modulation of this cascade by S-nitrosation of MIF has the potential to prevent HF after AMI

缺血性心力衰竭（HF）由于缺血性心脏病是西方世界死亡的主要原因。在心肌缺血和再灌注（I/R）之后，先天免疫反应的激活是限制心脏损伤程度和促进愈合程度的重要组成部分。在心肌中募集中性粒细胞和单核细胞表示愈合的第一步，然后单核细胞分化为巨噬细胞。愈合需要将巨噬细胞的微观极化为修复和炎症物种。心肌I/R中控制单核细胞分化和巨噬细胞极化的机制尚不清楚。在I/R期间，与损伤相关的分子模式（湿）被从缺血性心肌释放出来，最近成为急性心肌梗塞（AMI）之后策划这种炎症反应的关键参与者。潮湿的受体（例如Toll样受体4（TLR4））触发炎症信号传导级联反应。巨噬细胞迁移抑制因子（MIF）是一种趋化因子样函数（CLF）趋化因子，这是一种新兴的分子类别，在功能上与介体类别的警报蛋白和潮湿的类别重叠。 MIF控制着白血病巨噬细胞中的TLR4表达，并且在心肌I/R期间也释放，并展示自动和内部的心脏保护活动。自己的研究最近表明，在再灌注的早期阶段，MIF的心脏保护是突出的，并且申请人将S-硝化作用确定为MIF（SNO-MIF）的新型翻译后修饰（SNO-MIF），该修饰增强了MIF的心脏保护特性，同时还调节了其在再生过程中其心脏组织分泌的分泌。 SNO-MIF是否改变了趋化特性，以及它是否影响I/R应力期间心脏中的单核细胞分化和巨噬细胞极化。在这里，申请人旨在调查MIF是否是心肌I/R期间与潮湿相关的免疫反应的调节剂，以及MIF的S-硝化调节是否有可能在AMI之后预防HF