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

缺血性心脏疾病引起的缺血性心力衰竭（HF）是西方世界死亡的主要原因。心肌缺血再灌注（I/R）后，先天免疫反应的激活是限制心脏损伤程度和促进愈合的重要组成部分。中性粒细胞和单核细胞向心肌募集是愈合的第一步，随后单核细胞分化为巨噬细胞。愈合需要巨噬细胞进一步分化为修复和炎症细胞。心肌I/R中单核细胞分化和巨噬细胞极化的调控机制尚不清楚。损伤相关分子模式（DAMPs）在I/R期间从缺血心肌释放，最近在急性心肌梗死（AMI）后的炎症反应中发挥了关键作用。DAMPs被toll样受体4 （TLR4）等模式识别受体识别，从而引发炎症信号级联反应。巨噬细胞迁移抑制因子（MIF）是一种趋化因子样功能（CLF）趋化因子，是一类新兴的分子，在功能上与警报器和DAMPs的中介类重叠。MIF控制TLR4在白血病巨噬细胞中的表达，也在心肌I/R期间释放，并表现出自身和内源性心脏保护活性。最近自己的研究表明，MIF的心脏保护作用在再灌注的早期阶段是突出的，申请人认为s -亚硝化是MIF的一种新的翻译后修饰（SNO-MIF），它增强了MIF的心脏保护特性，同时也调节了其在再灌注期间从心脏组织分泌。SNO-MIF是否改变了I/R应激时心脏的趋化特性以及是否影响单核细胞分化和巨噬细胞极化尚不清楚。在这里，申请人的目的是研究MIF是否是心肌I/R期间damps相关免疫反应的调节因子，以及MIF的s-亚硝化对这一级联的调节是否有可能预防AMI后的HF

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