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

缺血性心力衰竭（HF）作为缺血性心脏病的后果是西方世界的主要死亡原因。在心肌缺血和再灌注（I/R）后，先天免疫应答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的募集表示愈合的第一步，随后是单核细胞分化为巨噬细胞。愈合需要进一步微调极化巨噬细胞修复和炎症物种。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（DAMP）在I/R期间从缺血心肌释放，并且最近已成为急性心肌梗死（AMI）后协调这种炎症反应的关键参与者。DAMP被模式识别受体如Toll样受体4（TLR 4）识别，其触发炎症信号级联。巨噬细胞移动抑制因子（MIF）是一种趋化因子样功能（CLF）趋化因子，是一类新兴的分子，在功能上与警报素和DAMP介体类别重叠。MIF控制白血病巨噬细胞中TLR 4的表达，也在心肌I/R期间释放，并表现出自分泌和内分泌的心脏保护活性。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，并且申请人将S-亚硝化鉴定为MIF的新的翻译后修饰（SNO-MIF），其增强MIF的心脏保护性质，同时还调节其在再灌注期间从心脏组织的分泌。SNO-MIF是否具有改变的趋化特性以及它是否影响I/R应激期间心脏中的单核细胞分化和巨噬细胞极化尚不清楚。在此，申请人旨在研究MIF是否是心肌I/R期间DAMP相关免疫应答的调节剂，以及通过MIF的S-亚硝化调节该级联是否具有预防AMI后HF的潜力

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